Schizophrenia: A neurodevelopmental disorder — Integrative genomic hypothesis and therapeutic implications from a transgenic mouse model

Schizophrenia Research 143 (2013) 367–376

Contents lists available at SciVerse ScienceDirect

Schizophrenia Research journal homepage: www.elsevier.com/locate/schres

Review

Schizophrenia: A neurodevelopmental disorder — Integrative genomic hypothesis and therapeutic implications from a transgenic mouse model M.K. Stachowiak a,⁎, A. Kucinski a, R. Curl a, C. Syposs a, Y. Yang b, S. Narla a, C. Terranova a, D. Prokop a, I. Klejbor c, M. Bencherif d, B. Birkaya a, T. Corso e, A. Parikh f, E.S. Tzanakakis f, S. Wersinger a, b, E.K. Stachowiak a,⁎ a Molecular and Structural Neurobiology & Gene Therapy Program, Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, SUNY, Buffalo, NY, USA b Department of Psychology, SUNY, Buffalo, NY, USA c Gdansk Medical University, Gdansk, Poland d Targacept Inc., Winston-Salem, NC 27101, USA e Lake Erie College of Osteopathic Medicine, Erie, PA, USA f Department of Chemical and Biological Engineering, Western New York Stem Cell Culture and Analysis Center, SUNY, Buffalo, NY, USA

a r t i c l e

i n f o

Article history: Received 29 June 2012 Received in revised form 2 November 2012 Accepted 6 November 2012 Available online 8 December 2012 Keywords: Fibroblast growth factor receptor 1 Nicotinic acetylcholine receptors Transgenic mouse model of schizophrenia Midbrain dopamine neurons Atypical neuroleptics α7 nicotinic receptors

a b s t r a c t Schizophrenia is a neurodevelopmental disorder featuring complex aberrations in the structure, wiring, and chemistry of multiple neuronal systems. The abnormal developmental trajectory of the brain appears to be established during gestation, long before clinical symptoms of the disease appear in early adult life. Many genes are associated with schizophrenia, however, altered expression of no one gene has been shown to be present in a majority of schizophrenia patients. How does altered expression of such a variety of genes lead to the complex set of abnormalities observed in the schizophrenic brain? We hypothesize that the protein products of these genes converge on common neurodevelopmental pathways that affect the development of multiple neural circuits and neurotransmitter systems. One such neurodevelopmental pathway is Integrative Nuclear FGFR1 Signaling (INFS). INFS integrates diverse neurogenic signals that direct the postmitotic development of embryonic stem cells, neural progenitors and immature neurons, by direct gene reprogramming. Additionally, FGFR1 and its partner proteins link multiple upstream pathways in which schizophrenia-linked genes are known to function and interact directly with those genes. A th-fgfr1(tk-) transgenic mouse with impaired FGF receptor signaling establishes a number of important characteristics that mimic human schizophrenia — a neurodevelopmental origin, anatomical abnormalities at birth, a delayed onset of behavioral symptoms, deficits across multiple domains of the disorder and symptom improvement with typical and atypical antipsychotics, 5-HT antagonists, and nicotinic receptor agonists. Our research suggests that altered FGF receptor signaling plays a central role in the developmental abnormalities underlying schizophrenia and that nicotinic agonists are an effective class of compounds for the treatment of schizophrenia. © 2012 Elsevier B.V. All rights reserved.

1. Schizophrenia: a neurodevelopmental disease Schizophrenia is a debilitating psychiatric disorder affecting 1% of the population. The scope and complexity of the disease are profound — there are broad anatomical and chemical changes across the neuroaxis including: ventricular enlargement, malformed cortical and subcortical structures and impaired neurotransmission of dopaminergic, GABAergic, glutamatergic and serotonergic systems (Wong and Van Tol, 2003; Carlsson, 2006). Behavioral symptoms often follow a predictable time ⁎ Corresponding authors at: Department of Pathology and Anatomical Sciences, SUNY, 3435 Main Street, 206A Farber Hall, Buffalo, NY 14214, USA. Tel.: +1 716 829 3540. E-mail addresses: [email protected] (M.K. Stachowiak), [email protected] (E.K. Stachowiak). 0920-9964/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2012.11.004

course with cognitive impairments such as memory and attention deficits, typically appearing in childhood, and positive symptoms (psychotic episodes) and negative symptoms, such as social and motivational deficits manifesting in late adolescence or early adulthood. Consistent with a complex phenotype that has not been fully described the etiology of the disease remains largely unknown. A neurodevelopmental hypothesis postulates that interactions between multiple genes trigger a cascade of neuropathological events, beginning during gestation and progressing into adulthood, which may be initiated and directed by environmental factors (Murray and Lewis, 1987; Thompson et al., 2004; Fatemi and Folsom, 2009; Sun et al., 2010; Rapoport et al., 2012). A network of some 160 genes selected from linkage, association, and gene expression literature reports have been proposed to contribute to the etiology of the disease (Sun et al., 2010;

368

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376

Rodriguez-Murillo et al., 2012). These genes mediate a wide range of neurodevelopmental events including progenitor cell proliferation and differentiation, migration, cytoskeleton reorganization, axonal connectivity and patterning of brain structures (Jaaro-Peled et al., 2009; Moskvina et al., 2009; Potkin et al., 2010; Sun et al., 2010; Ayalew et al., 2012). 2. Fibroblast growth factor receptor 1 — a point of convergence in neurodevelopmental pathways How does the altered expression pattern of diverse genes, each with broad and unique functions in neurodevelopment, contribute to the complex conglomerate of abnormalities observed in schizophrenia? One possibility is that the protein products of affected genes converge on shared neurodevelopmental pathways that influence the growth and patterning of common neural circuits and brain structures. For example, schizophrenia genes operate within 24 known pathways that are critical for neuronal development and share common pathway elements including cAMP, Ca++/PKC, MAPK and RXR signaling (Feng et al., 2005; Wong et al., 2011; Ayalew et al., 2012; Rodriguez-Murillo et al., 2012). In our laboratory we have characterized a candidate mechanism that links multiple upstream pathways in which schizophrenia-linked genes are known to function — the “Integrative Nuclear Fibroblast Growth Factor Receptor 1 Signaling” (INFS) pathway (for review see Stachowiak et al., 2007a, 2011). INFS regulates genes through direct interaction with transcription gating factor CREB-Binding Protein (CBP). In INFS, FGFR1 and its ligand, FGF-2,translocateinto the nuclear interior (Maher, 1996; Stachowiak et al., 1996; Myers et al., 2003; Dunham-Ems et al., 2009) (see for example Fig. 1C) initiating gene activation and epigenetic changes (Carlezon et al., 2005; Stachowiak et al., 2007a). INFS links CBP to multiple upstream pathways such as cAMP, Ca++/PKC, MAPK, (Stachowiak et al., 2003, 2007b, 2011) and nuclear retinoid and orphan Nur receptor-mediated pathways (Baron et al., 2012; Lee et al., 2012) (Fig. 1) In addition, our recent Chromatin Immuno-Precipitation (ChiP) experiments show broad binding of FGFR1 to genes linked with schizophrenia suggesting that disruptions in an INFS-controlled genomic circuit may underlie the etiology of the disorder (Fig. 1B). FGFs and their receptors (FGFRs) are involved in the growth and patterning of several brain structures during development (Reuss and von Bohlen und Halbach, 2003) and interact with numerous proteins associated with neurodevelopment (Williams et al., 2003; Flajolet et al., 2008; Terwisscha van Scheltinga et al., 2010). For example, FGFR interact with adenosine A2A receptors to activate the MAPK/ERK pathway leading to neurite extension, spine morphogenesis and corticostriatal plasticity (Flajolet et al., 2008; Terwisscha van Scheltinga et al., 2010). Classical genetics has demonstrated numerous links between FGF/FGFRs and schizophrenia (Jungerius et al., 2008; Shao and Vawter, 2008; O'Donovan et al., 2009; Terwisscha van Scheltinga et al., 2010) (Table 1). A recently large gene linkage study found an association between FGFR single nucleotide polymorphisms (SNPs) and schizophrenia (O'Donovan et al., 2009). Associations between FGF and other schizophrenia related genes such as glypican 1 (GPC1) (Potkin et al., 2010) and neuronal PAS domain protein 3 (NPAS3) (Kamnasaran et al., 2003) have been described. Altered FGF activity has been observed in the hippocampus (Gaughran et al., 2006; Turner et al., 2008), frontal cortex (Katsel et al., 2005) and blood serum (Hashimoto et al., 2003) of schizophrenia patients. Prenatal environmental stress known to contribute to schizophrenia alters FGF activity (Ganat et al., 2002; Dono, 2003; Fumagalli et al., 2005). Finally, a role of FGFs in the etiology of related psychiatric and mood disorders has been described (Riva et al., 2005; Turner et al., 2006, 2008). 3. Targeting FGFR1(TK-) to the dopaminergic system to create anatomical and neurochemical schizophrenia-like impairments Although multiple transmitter systems are altered in the schizophrenia brain, the hypoplasia and abnormal activity of the dopamine (DA)

systems remains an established pathological hallmark of the disease and a central therapeutic target (Howes and Kapur, 2009). FGF is critical in mediating the developing DA (Grothe and Timmer, 2007) and midbrain systems (Trokovic et al., 2003, 2005; Jukkola et al., 2006). We hypothesized that blockade of endogenous INFS in developing midbrain catecholaminergic neurons would alter the DA system and potentially trigger a secondary pathology in co-developing neuronal systems. Using dominant negative FGFR1(TK-), which was previously shown to block neuronal differentiation in neuronal progenitor cells in vitro (Fang et al., 2005), a transgenic mouse was engineered, thfgfr1(tk-). FGFR1(TK-) was targeted to DA-producing cells of the SNc (which project to striatum) and VTA (which project to nucleus accumbens and cortex) by fusion with the 4.8 kb tyrosine hydroxylase (TH) promoter (Klejbor et al., 2006). The reduced developmental FGFR1 signaling gave rise to smaller and less dense adult midbrain DA neurons relative to age-matched controls (Klejbor et al., 2006) (Fig. 2). In humans not subjected to neuroleptic treatment there is a significantly reduced volume of SNc area (−21%) and reduced mean nerve cell volume in the SNc (−15%) and VTA (−17%) (Bogerts et al., 1983). Furthermore pathology of neuronal processes of midbrain neurons has been demonstrated (Ikemoto et al., 2009). Adult th-fgfr1(tk-) mice also have reduced dopamine transporter protein (DAT) immunofluorescence in the striatum, indicating innervation by fewer DA terminals. Despite these reductions, paradoxically, there were increased levels of DA and DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatal tissue of adult th-fgfr1(tk-) mice, suggesting DA hypertransmission (Klejbor et al., 2006). This was further confirmed in vivo as elevated striatal DA release was observed during a sensorimotor gating task measured (Kucinski et al., 2012), which is in line with excessive DA transmission during psychotic episodes in schizophrenia patients (Laruelle et al., 1999). The increased striatal DA transmission in th-fgfr1(tk-) mice are also consistent with human PET studies(Meyer-Lindenberg et al., 2002) and postmortem evidence of increased subcortical DA synthesis in schizophrenia (Toru et al., 1982; Mueller et al., 2004). How DA neuronal hypoplasia could paradoxically lead to DA hypertransmission in the subcortical basal ganglia? Although much work remains, one potential mechanism could involve the reduced striatal expression of DAT in transgenic mice(Klejbor et al., 2006) resulting in diminished overall striatal DA reuptake activity, thereby effectively increasing extracellular striatal DA content as observed in partially 6-hydroxydopamine lesioned rats (Zigmond et al., 1984). Importantly, DAT has been implicated in the pathology of SZ (Zheng et al., 2012). We further demonstrated that blockade of INFS in developing DAproducing neurons altered serotonergic anatomy and transmission. In the developing brain, serotonin (5-HT) and DA systems compete for neuronal target sites and a dynamic relationship between the two systems persists into adulthood (Stachowiak et al., 1984; Bruno et al., 1987; Rodriguez-Pallares et al., 2003). In FGFR1 knockout embryos and adult mice there was a caudal shift in embryonic and adult midbrain DA neurons and an increase in 5-HT neurons in that region (Jukkola et al., 2006). Quantitative immunohistology of adult th-fgfr1(tk-) mice revealed hyperinnervation of hypoplastic midbrain DA neurons by serotonergic terminals (Fig. 2). This was corroborated by increased tissue levels of 5-HT and 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the SN and VTA of adult transgenic mice. Evidence suggests an overactive 5-HT system in schizophrenia (Bartfai et al., 1983; Hansson et al., 1994) (for discussion see also Klejbor et al., 2009) and drugs that target 5-HT receptors, including atypical antipsychotics (AAP), are efficacious against positive schizophrenia symptoms attributable to dopaminergic hypertransmission (Bartfai et al., 1983; Schmidt et al., 1993; Abel et al., 1996; Lieberman et al., 1998; Harrison, 1999). In th-fgfr1(tk-) mice, the hyperinnervation of SNr by 5-HT terminals may also contribute to DA hypertransmission (Klejbor et al., 2009). Disorganization of cortical layers and their myelinated connecting tracks is another commonly described pathology in human schizophrenia

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376

369

Fig. 1. INFS integrates signals* of diverse SZ linked genes and pathways. (A) “Feed-forward-and-gate” signaling modules of INFS for neuronal differentiation integrates pathways affected in SZ (Stachowiak et al., 2007a, 2011). Neurogenic signals generated by diverse extracellular stimuli (St; neurotransmitters, hormones, growth factors, cell contact receptors) in embryonic and brain stem cells are propagated through signaling pathways (SiP; cAMP, Ca++/PKC, MAPK) to sequence specific transcription factors [(ssTF; CREB, AP1, NfkB, Smads, nuclear retinoid receptors (RXR/ RAR) and orphan Nur receptors)]. In parallel, a newly synthesized FGFR1 translocates into the nucleus and “feeds forward” (F-F) neurogenic signals directly to CREB binding protein (CBP), an essential transcriptional co-activator and gene-gating factor. The coupled activation of CBP by nuclear (n) FGFR1, known as Integrative Nuclear FGFR1 Signaling (INFS), and cascade signal transduction to ssTF are responsible for cell differentiation. *Marks signaling pathways in which schizophrenic-related genes have been found, including cAMP, G-protein signaling, PKC, MAPK, NfkB, CREB, RXR, and Nurr1 (Sun et al., 2010; Buervenich et al., 2000; Jablensky et al., 2011), which have also been shown to engage INFS (Stachowiak et al., 2007a, 2011; Baron et al., 2012; Lee et al., 2012). (B) Our recent Chromatin Immuno-Precipitation-sequencing (ChIP-seq) analysis shows broad binding of FGFR1 to genes linked with schizophrenia (manuscript in preparation). The binding of FGFR1, RXR, Nur77 and histone 3 variant H3.3 to potential Nur/RXR target regions in selected schizophrenia-linked genes: DISC1, ZEP365, ANK3 was verified by independent ChIP experiments in human (h) ESC as shown. The analysis was performed as described in Lee et al. (2012) and Baron et al. (2012). qPCR was used to determine relative amount of specific loci in FGFR1, RXR, Nur77 or H3.3 antibody immunoprecipitates (IP), Input, and IgG (preimmune) samples. Data are expressed as IP/input where ΔΔCt=(CtInput −CtIP Ab)/(CtInput −CtIP IgG). Bars illustrate RA-induced increase of FGFR1 biding to the indicated regions of the genes. In pluripotent nondifferentiated hESC (control) FGFR1 binds along with its partners RXR and Nur77 and with H3.3, a marker of transcribed chromatin to DSIC1 and ZFP365, with little or no binding to ANK3. The FGFR1/RXR and FGFR1/Nur77 complexes are known to activate transcription (Baron et al., 2012; Lee et al., 2012) and thus may support the DISC1, and ZEP365 gene activities. During differentiation induced by 1 μM all-trans retinoic acid (RA) (48 h treatment) an increased binding of FGFR1 and disassociation of RXR, Nur77 and H3.3 from these genes are observed. Increased binding of FGFR1, which alone lacks a transactivating function (Fang et al., 2005; Lee et al., 2012), may act to repress gene activities. Thus it appears that FGFR1 plays a direct role in the regulation of neurodevelopmental genes linked to schizophrenia. Together our observations suggest a complete transcriptional circuit in which INFS integrates the incoming developmental signals (St) through the feed-forward (FF) module and reinforces/turns off those input signals via a feedback (FB) module (Stachowiak, 2012). We propose that SZ mutations, including “weak” copy variations may deregulate this self-controlled genomic circuit and thus lead to broad molecular and developmental dysfunctions. (C) Activation of INFS illustrated by an accumulation of FGFR1 in the nuclei of cultured human neural progenitor cells. 1 — Control; 2 — cells treated with 1 μM α7 neuronal nicotinic receptor agonist TC7020 for 48 h.

(Rodriguez-Murillo et al., 2012). The formation of cortical layers and cell connectivity are governed by timely regulation of ventricular germinal cells mitoses and exit from the cell cycle. DA terminals that innervate the striatum lie adjacent to the lateral ventricles where neural stem/ progenitor cells reside and shown to influence biology of these germinal cells (Popolo et al., 2004). Indeed, in several transgenic mice across

multiple generations we observed a distortion in cortical layering. Stereological analysis of the anterior cingulated area of the brain cortex verified reduced densities of NeuN positive neurons in th-fgfr1(tk-) mice versus control C57bl/6J animals, which were confined to the first three layers — molecular, granular and outer pyramidal of the cortex. Moreover, cells with granular neuronal morphology were displaced

370

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376

Table 1 FGFR1 and FGF-2 mutations in schizophrenia and related Kallmann syndrome. Gene

Polymorphism/mutation

P-value

Disease

FGFR1

SNP rs3925 SNP rs6987534 SNP rs7012413 Multiple mutations SNP rs12506776 SNP rs7700205

0.0049 0.0079 0.105 – 0.0048 0.0699

SZ* SZ* SZ* KS** SZ*** SZ***

FGF2

SZ — schizophrenia (*Jungerius et al., 2008; ***O'Donovan et al., 2009; KS — Kallmann Syndrome with multiple FGFR1 mutations co-segregates with schizophrenia; **Cowen and Green, 1993; Vagenakis et al., 2004; Albuisson et al., 2005).

into the superficial molecular layer and cortical stratification was less pronounced in transgenic mice. Thus, the hyperactivity of the nigrostriatal pathway might also perturb cortical development. Importantly, myelinated cortical fibers in th-fgfr1(tk-) mice were also disorganized. Neurons in these superficial layers integrate function of cortical columns and control the activities of glutamatergic projection neurons, which arise in deeper cortical layers and innervate to control striatal DA terminals and midbrain DA neurons. A disruption of these neurons has been proposed to play a role in sensory gating, cognitive and social behavior deficits in schizophrenia (Meyer-Lindenberg and Tost, 2012). In summary, impaired development of DA neurons affects neuronal systems which are innervated by DA neurons or receive DA input indicating that developmental hypoplasia of DA neurons can lead to wide spread structural brain disorganization as observed in schizophrenia (Fig. 2).

4. th-fgfr1(tk-) mice display positive, negative and cognitive SZ-like symptoms Adult th-fgfr1(tk-) mice exhibit reduced auditory prepulse inhibition (PPI) of the startle response (Fig. 3A), a well-established endophenotypic marker of schizophrenia (Braff et al., 2001; Swerdlow et al., 2008). PPI is a measure of sensorimotor gating response, which functionally serves as a filter of sensory information and allows the organism to properly organize and prioritize sensory information in order to make proper motor responses to environmental cues. It was shown that the extent of PPI impairment in schizophrenia correlates with cognitive dysfunction such as reduced attention as well as positive symptoms such as hallucinations and delusions (Braff et al., 1999), suggesting reduced PPI lies at the interface of both types of symptoms. Reduced PPI is generally attributed to subcortical hyperdopaminergic transmission and can be induced by administration of DA agonists (Swerdlow et al., 1998; Powell et al., 2009) and is also observed in other rodent models of schizophrenia with DA hyper-transmission, such as DAT knockout mice (Ralph et al., 2001; Geyer et al., 2002; Powell et al., 2009). Furthermore, we found that impaired PPI in th-fgfr1(tk-) mice is accompanied by increased striatal DA release as measured by in vivo microdialysis during an acoustic PPI test (Kucinski et al., 2012), indicating enhanced stimulus-induced DA release in the dorsal striatum underlies the impaired sensorimotor gating. Psychotic symptoms in schizophrenia do not typically appear until late adolescence/early adulthood despite the presence of genetic and anatomical abnormalities at birth (Wong and Van Tol, 2003; Thompson et al., 2004). This suggests that underlying pathology progresses during postnatal life but lies dormant until the brain matures to functionally incorporate ‘misconstructed’ neuronal systems. In each case, environmental events may provide disease-revealing mechanisms (Murray and Lewis, 1987; Fatemi and Folsom, 2009). In th-fgfr1(tk-) mice, reduced PPI does not appear until approximately 4 months of age relative to controls (Fig. 3A). This delayed onset coincides with evolving neurochemical changes in transgenic mice. For example, increased tissue levels of DA in the striatum and 5-HT in the midbrain relative to controls are not observed until adulthood (Klejbor et al., 2006, 2009). Thus, the

developmental DA-th-fgfr1(tk-) model uniquely recreates a temporal aspect of the human disease. Characteristic to human schizophrenia is the disruption of social interactions and the inability to form new contacts (negative symptom). The th-fgfr1(tk-) mice displayed reduced social interaction in a resident-intruder paradigm, not attributable to anxiety related behavior (Hauser et al., 2009; Klejbor et al., 2009) (Fig. 3C). Another key feature of schizophrenia is cognitive impairment, typically characterized by deficits in working memory (Davis et al., 1991; Goldman-Rakic et al., 2004). Using a behavioral paradigm that tests for temporal (recent versus old) components of working memory (DeVito et al., 2009), it was determined that th-fgfr1(tk-) mice were unable to distinguish between old and recently investigated objects, a distinction that was successfully made by control mice (Fig. 4), further suggesting working memory dysfunction. In summary, the th-fgfr1(tk-) mice display impairments that mimic cognitive dysfunction as well as the negative and positive symptoms of the human disease. These similarities create an effective model to investigate the effects of environment and epigenetics on disease progression and preventative therapies. 5. Behavioral symptoms in th-fgfr1(tk-) mice are correctible by typical anti-psychotic (TAP) and atypical antipsychotic (AAP) drugs The diminished sensory gating measured by PPI in adult th-fgfr1(tk-) mice was effectively restored with administration of typical antipsychotic (TAP) flupentixol, a DA antagonist (Klejbor et al., 2006), consistent with striatal hypertransmission of DA. We further explored the significance of 5-HT axonal hyperplasia in adult th-fgfr1(tk-) mice by analyzing the therapeutic effects of atypical antipsychotics (AAP), which target a variety of receptor subtypes, including 5-HT receptors as well as specific 5-HT2A antagonist M100907. AAP clozapine (Fig. 3B), quietapine, and M100907 normalized PPI and startle impairments in transgenic mice (Klejbor et al., 2009). Interestingly, quetiapine, but not clozapine, improved social withdrawal mimicking findings in human patients (Zhong et al., 2006). M100907 also improved social interaction deficits (not shown) (Klejbor et al., 2009). We hypothesized that 5-HT2A antagonism improved PPI deficits in th-fgfr1(tk-) mice by attenuating the inhibitory influence of hyperinnervating 5-HT fibers onto GABAergic interneurons of the SNr, thus increasing inhibition of SNc midbrain neurons and subsequently decreasing DA release into the striatum. Simultaneously, blockade of 5-HT2A receptors directly on the somatodendritic regions of VTA neurons may increase 5-HT-mediated DA release in the frontal cortex and improve social withdrawal (Klejbor et al., 2009). These findings support further development of 5-HT2A antagonists as therapeutic agents to treat disruption of social interactions in schizophrenia and other related disorders. 6. The nicotinic acetylcholine system in schizophrenia — an alternative target for schizophrenia therapy Due to the complexity of neurochemical and behavioral abnormalities in schizophrenia and shortcomings of common neuroleptics, most notably the inability to treat cognitive impairment and negative symptoms, alternative therapeutic targets are being explored to supplement or supplant current therapy options. One such target is the nicotinic acetylcholine (ACh) system. Schizophrenia patients smoke at a remarkably high rate and volume relative to the general population (Tidey et al., 2005; Dome et al., 2010; Williams et al., 2010). Numerous studies confirm that the primary psychoactive chemical in cigarette smoke, nicotine, improves a wide-range of cognitive functions and enhances emotionality and motivation (Stolerman et al., 2000; Adan et al., 2004; Harris et al., 2004; Newhouse et al., 2004; Levin et al., 2006). Nicotine was also shown to reverse haloperidol-related cognitive impairments in tests assessing memory and reaction time (Levin et al., 1996). Due

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376

371

Fig. 2. Brain malformations in th-fgfr1(tk-) mice. Brain structures: 1 — SN, 2 — VTA, 3 — striatum, 4 — anterior cingulate cortex, 5 — hippocampus, pyramidal layer. DA systems: Examples of tyrosine hydroxylase (TH) immunoreactive (IR) fluorescent DA neurons in midbrain nuclei at postnatal day (PD) 360 of control and th-fgfr1(tk-) mice are shown. Stereological counting and measurements revealed reduced size of DA neurons at PD 0 (SNc −27%, VTA −21%) and at PD 360 (SNc −15%, VTA −10%). Density of DA neurons was reduced at PD 0 (SNc −26%, VTA −34%) and at PD 360 (SNc −34%). Density of terminals in striatum (3) expressing DA transporter protein (DAT) was reduced by 23% in th-fgfr1(tk-) mice (all differences are statistically significant) (Klejbor et al., 2006). 5-HT systems: 5-HT-IR fluorescent cellular element neurons in midbrain nuclei of 12 months (PD 180) old mice. Brain sections were stained with anti-5-HT polyclonal Ab and Cy3 conjugated secondary Ab. Examples of 5-HT immunostaining in the VTA paranigral nucleus and substantia nigra pars reticulate (SNr) are shown. The 5-HT-IR fibers innervating the VTA or SN are predominantly smooth with small varicosities and thus similar to the D-type produced by the dorsal raphe nucleus (Fibiger and Miller, 1977; van der Kooy and Hattori, 1980). The PN has a dense network of long 5-HT-IR fibers with small varicosities, numerous puncta and smooth fibers without varicosities. In th-fgfr1(tk-) mice stereological counts revealed an increased number of incoming 5-HT fibers in the paranigral nucleus (1) and the parabrachial pigmentosus nucleus of the VTA, as well as in the SNr (2) when compared to controls. These axons formed dense networks of 5-HT-IR fibers with numerous varicosities. Also, using HPLC analysis we found increased levels of 5-HT in the SN and increased 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the VTA of adult th-fgfr1(tk-) mice (from: Klejbor et al., 2009). Cortical system (PD180): Gray matter staining cortical neurons with anti-NeuN antibody and stereological counting revealed −7.5% reduction of neuronal density in the anterior cingulate region. Subregional analysis of cortical layers revealed a 35% increase of NeuN+ cells and a 22% increase in DAPI+ cells in superficial cortical layers (layers 1 and 2 sampled). Black-Gold II staining displayed more myelinated, disorganized fibers in th-fgfr1(tk-) mice compared to nontransgenic controls (S. Narla, C. Syposs, E.K. Stachowiak — previously unpublished observations). Hippocampal pyramidal layer: Neurons stained with anti-NeuN. Preliminary analyses suggest reduced densities of pyramidal neurons in th-fgfr1(tk-) mice.

372

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376

Fig. 3. Impaired sensory-gating and social behavior in th-fgfr1(tk-) mice and their normalization by drugs.(A) Deficits in sensory gating appear in adulthood and are reversed by clozapine. Time dependent changes in prepulse inhibition (PPI) of control (n=12) and th-fgfr1(tk-) mice (n=12). There were no significant differences between the genotypes until 4 months. At 6 and 8.5 month groups there were significant reductions in PPI in th-fgfr1(tk-) mice at each prepulse intensity. *Significant difference between control and th-fgfr1(tk-) mice at individual stimulus intensity (post hoc; pb 0.05 after significant main effect of genotype F value; ANOVA). (B) A single injection of clozapine at 3.0 mg/kg i.p. significantly improves PPI in th-fgfr1(tk-) mice but has no effect on control mice. n=16 control and n=16 th-fgfr1(tk-) mice injected with clozapine at 0.5 mg/kg or 3.0 mg/kg, *Significant difference from control group receiving same treatment at individual stimulus intensity (post hoc; pb 0.05 after significant main effect of genotype F value; ANOVA). #Significant difference within genotype from vehicle group at individual stimulus intensity (post hoc; pb 0.05 after significant main effect of drug F value; ANOVA). There was a treatment×genotype interaction with clozapine treatment at 3.0 mg/kg (pb 0.05). (C) Effects of treatment with TC-5619 or TC-5619 combined with clozapine on social investigation (acute drug injections). In the absence of drug (baseline and vehicle groups), control mice spend more time investigating stimulus animals (nontransgenic mice) than th-fgfr1(tk-) mice. TC-5619 (0.3 mg/kg) increased the time both genotypes spent investigating the stimulus animal. There was no difference in investigation time between drug-treated control mice and drug-treated TK-mice. Low doses of clozapine (3.0 mg/kg) or TC-5619 (0.1 mg/kg) alone have no effect on investigation time of either a female or male stimulus animal. These behaviorally inactive doses of TC-5619 and clozapine administered together increase social investigation of female stimulus animals in both genotypes. †Significantly different from other groups of the same genotype (pb 0.05). *Significantly different from control group of the same treatment (pb 0.05). (A and B are from Klejbor et al., 2009; C is from Hauser et al., 2009).

to the heavy reliance of schizophrenic patients on cigarettes to improve negative symptoms and cognitive dysfunction, smoking is generally considered a form of self-medication (Leonard et al., 2007; Winterer, 2010).

Smoking and nicotine administration also improves reduced PPI in schizophrenic patients (Kumari et al., 2001; Postma et al., 2006; Woznica et al., 2009), an effect mediated by central neuronal nicotinic receptors (NNRs) (George et al., 2006). It was shown that nicotine's

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376

373

in working memory. Recent reports have suggested that the dorsal striatum plays an important role in cognitive function mediated by DA activity (Simpson et al., 2010; Cools, 2011). The improvement of working memory by TC-7020 in th-fgfr(tk-) mice may be associated with the normalization of hyperactive DA release in the dorsal striatum by α7 NNR agonism as previously demonstrated (Kucinski et al., 2012). It was also shown that α7 NNR agonism and an α7 allosteric potentiator increased DA release in the PFC of rats (Livingstone et al., 2009), an effect that could potentially mediate and enhance executive functions such as working memory and attention (Schultz, 2002; Floresco and Magyar, 2006). Thus, agonism of α7 NNRs may facilitate the normalization of impaired DA transmission in multiple brain regions and offer the possibility that α7 nicotinic-targeting compounds improve cognitive function in human patients. 7. Conclusions Fig. 4. TC-7020 improves a measure of cognition that is impaired in th-fgfr1(tk-) mice. During Phase I, mice were placed into the arena for 10 min and allowed to investigate four identical “old” objects. Subjects were then returned to their home cage for 50 min. During Phase II, four “new” identical objects were placed in the arena and mice were given 10 min to explore the objects. After returning to their home cages again, mice were then injected with either saline or TC-7020 (1.0 mg/kg, i.p.). 40 min after injections, mice were placed in the arena for Phase III and investigation time of each object (2 “old” and 2 “new”) was measured. In subjects with no impairments, it is common to spend more time investigating the old objects presented in Phase I, which are less familiar than the more recent objects from Phase II (“new” objects). With saline, male th-fgfr1(tk-) mice cannot distinguish between objects presented in the recent (Phase II, “B” objects) and in the distant past (Phase I, “A” objects). This deficit may reveal working memory impairment. In mice administered TC7020, this deficit was ameliorated. Bars represent means+/−SEM. *Significantly greater than recent, one way ANOVA (pb 0.05). Preliminary account of these observations was given in Yi Yang et al. (2010).

reversal of DA agonist-induced PPI deficits in rodents was blocked with α7 NNR antagonist methyllycaconitine (MLA) (Suemaru et al., 2004). A promoter mutation in the α7 NNR gene (CHRNA7) is found more frequently in schizophrenic and bipolar patients as well as individuals with sensorimotor gating deficits (Leonard et al., 2002, 2007; Martin et al., 2007). In addition, post-mortem studies show reduced expression of α7 NNRs in the PFC and hippocampus of schizophrenic patients (Guan et al., 1999; Freedman et al., 2000). In th-fgfr1(tk-) mice, selective α7 NNR agonists TC-5619 and TC-7020 (Marrero et al., 2010) improved PPI and startle impairments (Hauser et al., 2009; Kucinski et al., 2012) while other α7 NNR agonists have also been shown to increase PPI in other mouse models of schizophrenia (Hajos et al., 2005; Acker et al., 2008; Tietje et al., 2008; Kohnomi et al., 2010; Wallace et al., 2011). Uniquely, in th-fgfr1(tk-) mice it was determined that acute administration of α7 NNR agonist TC-7020 normalized excessive striatal DA release during PPI testing, directly demonstrating an α7 NNR-mediated suppression of schizophrenia-associated hyperdopaminergic innervation (Kucinski et al., 2012). Furthermore, TC-5619 improved social interaction deficits in th-fgfr1(tk-) mice, an effect that was augmented by AAP clozapine which alone had no corrective action (Fig. 3C) (Hauser et al., 2009). A similar additive effect of clozapine and TC-5619 was also observed against the reduced PPI (Hauser et al., 2009) in which previous studies showed that nicotine enhanced clozapine's alleviating effects on PPI and other cognitive impairments (Levin et al., 2005; Levin and Rezvani, 2007). α7 NNRs are found on 5-HT neurons in the dorsal raphe and may influence 5-HT release (Aznar et al., 2005). Interestingly, 5-HT is an antagonist of α7-wild-type NNR through interactions at, or near the acetylcholine-binding sites (Fucile et al., 2002). Hence, α7 NNR agonists could function to overcome the potential suppression of α7 NNR activity by excessive 5-HT released from the hyperplastic 5-HT terminals (Table 2). We further sought to determine if administration of α7 NNR agonist TC-7020 would improve cognitive dysfunction in th-fgfr1(tk-) mice. Acute administration of TC-7020 increased investigation preference for old objects in transgenic animals (Fig. 4), suggesting an improvement

In conclusion, inhibition of INFS, a common neurodevelopmental mechanism that integrates several schizophrenia related pathways, recapitulates several anatomical, neurochemical and behavioral features of the human disease. Targeting of the dominant negative FGFR1(TK-) to developing postmitotic catecholamine neurons in which the INFS mechanism is activated impairs their development producing hypoplastic and hyperactive DA neurons. This initial abnormality is accompanied by secondary changes in other neuronal systems including brain stem serotonergic neurons and cortical neurons, which were not directly targeted by the FGFR1(TK-) transgene. Thus, in schizophrenia, malformation of DA neurons could be the initial defect that gradually affects other monoamine and cortical circuitries underlying the progression of the disease and gradual behavioral deterioration. Importantly, the onset of sensorimotor gating impairments in th-fgfr1(tk-) mice parallels the time course of positive symptom progression of the human disease. We also show that the nicotinic acetylcholine system has the potential to alleviate symptoms associated with both cortical and subcortical malformations by mediating subcortical DA release and possibly the activity of other neuronal networks impaired in schizophrenia. The concept of an integrative genomic circuit in the etiology of schizophrenia suggests a novel and generalized approach for the treatment of this polygenetic disease. Targeting a common signaling module such as the INFS, impeded by diverse genetic mutations, could potentially arrest the development of the multi-stage disorder. Transfection of a nuclear form of FGFR1 or its nuclear 23 kDa FGF-2 ligand in vivo using nanoparticle-mediated gene transfers effectively stimulates differentiation of neuronal progenitor cells in SVZ and cortical neurogenesis in adult brain (Stachowiak et al., 2009). An alternative or an additional approach could involve the development of small molecules that effectively activate the INFS module in brain stem cells when administered systemically. Candidate INFS-stimulating drugs including α7 NNR agonists, in addition to acutely correcting DA release and schizophrenicrelated behavioral impairments, display the capacity to activate the INFS mechanism as shown in our recent studies (Fig. 1C). Whether

Table 2 Summary of behavioral deficit drug effects in th-fgfr1(tk-) mice “+” indicates behavioral improvement and “–” a lack of therapeutic effect. AAP clozapine did not improve associality while quietapine produced significant improvement. Similar observations were made in human patients with schizophrenia. α7 NNR agonists reversed all three schizophrenia-like symptoms in th-fgfr1(tk-) mice. In addition, α7 NNR agonists enhanced the efficacy of AAP for reversing the PPI and social behavior deficits. *Only α7 NNR agonists were tested on cognition dysfunction in th-fgfr1(tk-) mice. In human schizophrenic patients TAP and AAP (Attard and Taylor, 2012; Fujimaki et al., 2012) (source) do not improve cognitive deficits while HT2A antagonists show positive effects (Poyurovsky et al., 2003).

Reduced PPI Reduced social interactions Impaired cognition*

TAP

AAP

5-HT2A antagonist

α7 NNR agonist

+ − −

+ −; + −

+ + +

+ + +

374

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376

such treatments could potentially rebuild neuronal networks and induce functional improvement in th-fgfr1(tk-) mice and the human disease awaits future investigation. Role of funding source This work was supported by NYSTEM contracts C026415 and C026714, University at Buffalo IRDF grants and March of Dimes and Birth Defects (FY97-0356) (to MKS). Contributors M.K. Stachowiak designed the manuscript and its studies. A. Kucinski participated in writing the manuscript. R. Curl participated in cognitive and working memory experiments. C. Syposs participated in stereological experiments, working memory experiments and in writing the manuscript. Y. Yang participated in working memory experiments. S. Narla participated in stereological experiments and in writing the manuscript. D. Prokop participated in immunocytochemical and stereological experiments. I. Klejbor participated in immunohistochemical and stereological experiments. M. Bencherif participated in experimental design, and planning pharmacological studies. B. Birkaya participated in molecular experiments and model development. T. Corso participated in neurochemistry. S. Wersinger designed and supervised behavioral experiments. E.K. Stachowiak designed and supervised neuroanatomical studies and in writing the manuscript. C. Terranova participated in molecular experiments and model development. A. Parikh participated in cell culture experiments. E.S. Tzanakakis participated in stem cell experiments. Conflict of interest Dr. Bencherif works for Targacept Inc. which produced TC7020 drug. The remaining authors declare no conflict of interest. Acknowledgements This work was supported by NYSTEM contracts C026415 and C026714, University at Buffalo IRDF grants and March of Dimes and Birth Defects (FY97-0356) (to MKS). We acknowledge Dr. Robert Miletich for his discussion of animal models of schizophrenia.

References Abel, K.M., O'Keane, V., Murray, R.M., 1996. Enhancement of the prolactin response to d-fenfluramine in drug-naive schizophrenic patients. Br. J. Psychiatry 168, 57–60. Acker, B.A., Jacobsen, E.J., Rogers, B.N., Wishka, D.G., Reitz, S.C., Piotrowski, D.W., Myers, J.K., Wolfe, M.L., Groppi, V.E., Thornburgh, B.A., Tinholt, P.M., Walters, R.R., Olson, B.A., Fitzgerald, L., Staton, B.A., Raub, T.J., Krause, M., Li, K.S., Hoffmann, W.E., Hajos, M., Hurst, R.S., Walker, D.P., 2008. Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl] furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity. Bioorg. Med. Chem. Lett. 18, 3611–3615. Adan, A., Prat, G., Sanchez-Turet, M., 2004. Effects of nicotine dependence on diurnal variations of subjective activation and mood. Addiction 99, 1599–1607. Albuisson, J., Pecheux, C., Carel, J.C., Lacombe, D., Leheup, B., Lapuzina, P., Bouchard, P., Legius, E., Matthijs, G., Wasniewska, M., Delpech, M., Young, J., Hardelin, J.P., Dode, C., 2005. Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2). Hum. Mutat. 25, 98–99. Attard, A., Taylor, D.M., 2012. Comparative effectiveness of atypical antipsychotics in schizophrenia: what have real-world trials taught us? CNS Drugs 26, 491–508. Ayalew, M., Le-Niculescu, H., Levey, D.F., Jain, N., Changala, B., Patel, S.D., Winiger, E., Breier, A., Shekhar, A., Amdur, R., Koller, D., Nurnberger, J.I., Corvin, A., Geyer, M., Tsuang, M.T., Salomon, D., Schork, N.J., Fanous, A.H., O'Donovan, M.C., Niculescu, A.B., 2012. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol. Psychiatry 17, 887–905. Aznar, S., Kostova, V., Christiansen, S.H., Knudsen, G.M., 2005. Alpha 7 nicotinic receptor subunit is present on serotonin neurons projecting to hippocampus and septum. Synapse 55, 196–200. Baron, O., Foerthmann, B., Lee, Y.W., Terranova, C., Ratzka, A., Stachowiak, E.K., Grothe, C., Claus, P., Stachowiak, M.K., 2012. Cooperation of nuclear FGFR1 and Nurr1 offers a new interactive mechanism in postmitotic development of mesencephalic dopaminergic neurons. J. Biol. Chem. 287, 19827–19840. Bartfai, A., Levander, S.E., Sedvall, G., 1983. Smooth pursuit eye movements, clinical symptoms, CSF metabolites, and skin conductance habituation in schizophrenic patients. Biol. Psychiatry 18, 971–987. Bogerts, B., Hantsch, J., Herzer, M., 1983. A morphometric study of the dopamine-containing cell groups in the mesencephalon of normals, Parkinson patients, and schizophrenics. Biol. Psychiatry 18, 951–969. Braff, D.L., Swerdlow, N.R., Geyer, M.A., 1999. Symptom correlates of prepulse inhibition deficits in male schizophrenic patients. Am. J. Psychiatry 156, 596–602. Braff, D.L., Geyer, M.A., Swerdlow, N.R., 2001. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl.) 156, 234–258.

Bruno, J.P., Jackson, D., Zigmond, M.J., Stricker, E.M., 1987. Effect of dopamine-depleting brain lesions in rat pups: role of striatal serotonergic neurons in behavior. Behav. Neurosci. 101, 806–811. Buervenich, S., Carmine, A., Arvidsson, M., Xiang, F., Zhang, Z., Sydow, O., Jonsson, E.G., Sedvall, G.C., Leonard, S., Ross, R.G., Freedman, R., Chowdari, K.V., Nimgaonkar, V.L., Perlmann, T., Anvret, M., Olson, L., 2000. NURR1 mutations in cases of schizophrenia and manic-depressive disorder. Am. J. Med. Genet. 96, 808–813. Carlezon Jr., W.A., Duman, R.S., Nestler, E.J., 2005. The many faces of CREB. Trends Neurosci. 28, 436–445. Carlsson, A., 2006. The neurochemical circuitry of schizophrenia. Pharmacopsychiatry 39 (Suppl. 1), S10–S14. Cools, R., 2011. Dopaminergic control of the striatum for high-level cognition. Curr. Opin. Neurobiol. 21, 402–407. Cowen, M.A., Green, M., 1993. The Kallmann's syndrome variant (KSV) model of the schizophrenias. Schizophr. Res. 9, 1–10. Davis, K.L., Kahn, R.S., Ko, G., Davidson, M., 1991. Dopamine in schizophrenia: a review and reconceptualization. Am. J. Psychiatry 148, 1474–1486. DeVito, L.M., Konigsberg, R., Lykken, C., Sauvage, M., Young III, W.S., Eichenbaum, H., 2009. Vasopressin 1b receptor knock-out impairs memory for temporal order. J. Neurosci. 29, 2676–2683. Dome, P., Lazary, J., Kalapos, M.P., Rihmer, Z., 2010. Smoking, nicotine and neuropsychiatric disorders. Neurosci. Biobehav. Rev. 34, 295–342. Dono, R., 2003. Fibroblast growth factors as regulators of central nervous system development and function. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R867–R881. Dunham-Ems, S.M., Lee, Y.W., Stachowiak, E.K., Pudavar, H., Claus, P., Prasad, P.N., Stachowiak, M.K., 2009. Fibroblast growth factor receptor-1 (FGFR1) nuclear dynamics reveal a novel mechanism in transcription control. Mol. Biol. Cell 20, 2401–2412. Fang, X., Stachowiak, E.K., Dunham-Ems, S.M., Klejbor, I., Stachowiak, M.K., 2005. Control of CREB-binding protein signaling by nuclear fibroblast growth factor receptor-1: a novel mechanism of gene regulation. J. Biol. Chem. 280, 28451–28462. Fatemi, S.H., Folsom, T.D., 2009. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr. Bull. 35, 528–548. Feng, J., Chen, J., Yan, J., Jones, I.R., Craddock, N., Cook Jr., E.H., Goldman, D., Heston, L.L., Sommer, S.S., 2005. Structural variants in the retinoid receptor genes in patients with schizophrenia and other psychiatric diseases. Am. J. Med. Genet. B Neuropsychiatr. Genet. 133B, 50–53. Fibiger, H.C., Miller, J.J., 1977. An anatomical and electrophysiological investigation of the serotonergic projection from the dorsal raphenucleus to the substantia nigra in the rat. Neuroscience 2, 975–987. Flajolet, M., Wang, Z., Futter, M., Shen, W., Nuangchamnong, N., Bendor, J., Wallach, I., Nairn, A.C., Surmeier, D.J., Greengard, P., 2008. FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity. Nat. Neurosci. 11, 1402–1409. Floresco, S.B., Magyar, O., 2006. Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacology (Berl.) 188, 567–585. Freedman, R., Adams, C.E., Leonard, S., 2000. The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J. Chem. Neuroanat. 20, 299–306. Fucile, S., Palma, E., Eusebi, F., Miledi, R., 2002. Serotonin antagonizes the human neuronal alpha7 nicotinic acetylcholine receptor and becomes an agonist after L248T alpha7 mutation. Neuroscience 110, 169–179. Fujimaki, K., Takahashi, T., Morinobu, S., 2012. Association of typical versus atypical antipsychotics with symptoms and quality of life in schizophrenia. PLoS One 7, e37087. Fumagalli, F., Bedogni, F., Slotkin, T.A., Racagni, G., Riva, M.A., 2005. Prenatal stress elicits regionally selective changes in basal FGF-2 gene expression in adulthood and alters the adult response to acute or chronic stress. Neurobiol. Dis. 20, 731–737. Ganat, Y., Soni, S., Chacon, M., Schwartz, M.L., Vaccarino, F.M., 2002. Chronic hypoxia upregulates fibroblast growth factor ligands in the perinatal brain and induces fibroblast growth factor-responsive radial glial cells in the sub-ependymal zone. Neuroscience 112, 977–991. Gaughran, F., Payne, J., Sedgwick, P.M., Cotter, D., Berry, M., 2006. Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder. Brain Res. Bull. 70, 221–227. George, T.P., Termine, A., Sacco, K.A., Allen, T.M., Reutenauer, E., Vessicchio, J.C., Duncan, E.J., 2006. A preliminary study of the effects of cigarette smoking on prepulse inhibition in schizophrenia: involvement of nicotinic receptor mechanisms. Schizophr. Res. 87, 307–315. Geyer, M.A., McIlwain, K.L., Paylor, R., 2002. Mouse genetic models for prepulse inhibition: an early review. Mol. Psychiatry 7, 1039–1053. Goldman-Rakic, P.S., Castner, S.A., Svensson, T.H., Siever, L.J., Williams, G.V., 2004. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl.) 174, 3–16. Grothe, C., Timmer, M., 2007. The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatal system. Brain Res. Rev. 54, 80–91. Guan, Z.Z., Zhang, X., Blennow, K., Nordberg, A., 1999. Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. Neuroreport 10, 1779–1782. Hajos, M., Hurst, R.S., Hoffmann, W.E., Krause, M., Wall, T.M., Higdon, N.R., Groppi, V.E., 2005. The selective alpha7 nicotinic acetylcholine receptor agonist PNU-282987 [N-[(3R)-1Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride] enhances GABAergic synaptic activity in brain slices and restores auditory gating deficits in anesthetized rats. J. Pharmacol. Exp. Ther. 312, 1213–1222. Hansson, L.O., Waters, N., Winblad, B., Gottfries, C.G., Carlsson, A., 1994. Evidence for biochemical heterogeneity in schizophrenia: a multivariate study of monoaminergic indices in human post-mortal brain tissue. J. Neural Transm. Gen. Sect. 98, 217–235.

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376 Harris, J.G., Kongs, S., Allensworth, D., Martin, L., Tregellas, J., Sullivan, B., Zerbe, G., Freedman, R., 2004. Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmacology 29, 1378–1385. Harrison, P.J., 1999. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122 (Pt 4), 593–624. Hashimoto, K., Shimizu, E., Komatsu, N., Nakazato, M., Okamura, N., Watanabe, H., Kumakiri, C., Shinoda, N., Okada, S., Takei, N., Iyo, M., 2003. Increased levels of serum basic fibroblast growth factor in schizophrenia. Psychiatry Res. 120, 211–218. Hauser, T.A., Kucinski, A., Jordan, K.G., Gatto, G.J., Wersinger, S.R., Hesse, R.A., Stachowiak, E.K., Stachowiak, M.K., Papke, R.L., Lippiello, P.M., Bencherif, M., 2009. TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochem. Pharmacol. 78, 803–812. Howes, O.D., Kapur, S., 2009. The dopamine hypothesis of schizophrenia: version III — the final common pathway. Schizophr. Bull. 35, 549–562. Ikemoto, K., Nishi, K., Kunii, Y., Wada, A., Yang, Q., Takase, I., Nishimura, A., Niwa, S., 2009. A study of monoamine neuronal systems of schizophrenic patients: using forensic autopsy brains. Leg. Med. (Tokyo) 11 (Suppl. 1), S165–S167. Jaaro-Peled, H., Hayashi-Takagi, A., Seshadri, S., Kamiya, A., Brandon, N.J., Sawa, A., 2009. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1. Trends Neurosci. 32, 485–495. Jablensky, A., Morar, B., Wiltshire, S., Carter, K., Dragovic, M., Badcock, J.C., Chandler, D., Peters, K., Kalaydjieva, L., 2011. Polymorphisms associated with normal memory variation also affect memory impairment in schizophrenia. Genes Brain Behav. 10, 410–417. Jukkola, T., Lahti, L., Naserke, T., Wurst, W., Partanen, J., 2006. FGF regulated gene-expression and neuronal differentiation in the developing midbrain–hindbrain region. Dev. Biol. 297, 141–157. Jungerius, B.J., Hoogendoorn, M.L., Bakker, S.C., Van't Slot, R., Bardoel, A.F., Ophoff, R.A., Wijmenga, C., Kahn, R.S., Sinke, R.J., 2008. An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia. Mol. Psychiatry 13, 1060–1068. Kamnasaran, D., Muir, W.J., Ferguson-Smith, M.A., Cox, D.W., 2003. Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J. Med. Genet. 40, 325–332. Katsel, P., Davis, K.L., Gorman, J.M., Haroutunian, V., 2005. Variations in differential gene expression patterns across multiple brain regions in schizophrenia. Schizophr. Res. 77, 241–252. Klejbor, I., Myers, J.M., Hausknecht, K., Corso, T.D., Gambino, A.S., Morys, J., Maher, P.A., Hard, R., Richards, J., Stachowiak, E.K., Stachowiak, M.K., 2006. Fibroblast growth factor receptor signaling affects development and function of dopamine neurons — inhibition results in a schizophrenia-like syndrome in transgenic mice. J. Neurochem. 97, 1243– 1258. Klejbor, I., Kucinski, A., Wersinger, S.R., Corso, T., Spodnik, J.H., Dziewiatkowski, J., Morys, J., Hesse, R.A., Rice, K.C., Miletich, R., Stachowiak, E.K., Stachowiak, M.K., 2009. Serotonergic hyperinnervation and effective serotonin blockade in an FGF receptor developmental model of psychosis. Schizophr. Res. 113, 308–321. Kohnomi, S., Suemaru, K., Goda, M., Choshi, T., Hibino, S., Kawasaki, H., Araki, H., 2010. Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the alpha(7) nicotinic acetylcholine receptor in Wistar rats. Brain Res. 1353, 152–158. Kucinski, A., Syposs, C., Wersinger, S., Bencherif, M., Stachowiak, M.K., Stachowiak, E.K., 2012. alpha7 neuronal nicotinic receptor agonist (TC-7020) reverses increased striatal dopamine release during acoustic PPI testing in a transgenic mouse model of schizophrenia. Schizophr. Res. 136, 82–87. Kumari, V., Soni, W., Sharma, T., 2001. Influence of cigarette smoking on prepulse inhibition of the acoustic startle response in schizophrenia. Hum. Psychopharmacol. 16, 321–326. Laruelle, M., Abi-Dargham, A., Gil, R., Kegeles, L., Innis, R., 1999. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol. Psychiatry 46, 56–72. Lee, Y.W., Terranova, C., Birkaya, B., Narla, S., Kehoe, D., Parikh, A., Dong, S., Ratzka, A., Brinkmann, H., Aletta, J.M., Tzanakakis, E.S., Stachowiak, E.K., Claus, P., Stachowiak, M.K., 2012. A novel nuclear FGF Receptor-1 partnership with retinoid and Nur receptors during developmental gene programming of embryonic stem cells. J. Cell. Biochem. 113, 2920–2936. Leonard, S., Gault, J., Hopkins, J., Logel, J., Vianzon, R., Short, M., Drebing, C., Berger, R., Venn, D., Sirota, P., Zerbe, G., Olincy, A., Ross, R.G., Adler, L.E., Freedman, R., 2002. Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch. Gen. Psychiatry 59, 1085–1096. Leonard, S., Mexal, S., Freedman, R., 2007. Smoking, genetics and schizophrenia: evidence for self medication. J. Dual Diagn. 3, 43–59. Levin, E.D., Rezvani, A.H., 2007. Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function. Biochem. Pharmacol. 74, 1182–1191. Levin, E.D., Wilson, W., Rose, J.E., McEvoy, J., 1996. Nicotine–haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology 15, 429–436. Levin, E.D., Petro, A., Caldwell, D.P., 2005. Nicotine and clozapine actions on pre-pulse inhibition deficits caused by N-methyl-D-aspartate (NMDA) glutamatergic receptor blockade. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 581–586. Levin, E.D., McClernon, F.J., Rezvani, A.H., 2006. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl.) 184, 523–539. Lieberman, J.A., Mailman, R.B., Duncan, G., Sikich, L., Chakos, M., Nichols, D.E., Kraus, J.E., 1998. Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol. Psychiatry 44, 1099–1117. Livingstone, P.D., Srinivasan, J., Kew, J.N., Dawson, L.A., Gotti, C., Moretti, M., Shoaib, M., Wonnacott, S., 2009. Alpha7 and non-alpha7 nicotinic acetylcholine receptors modulate dopamine release in vitro and in vivo in the rat prefrontal cortex. Eur. J. Neurosci. 29, 539–550.

375

Maher, P.A., 1996. Nuclear translocation of fibroblast growth factor (FGF) receptors in response to FGF-2. J. Cell Biol. 134, 529–536. Marrero, M.B., Lucas, R., Salet, C., Hauser, T.A., Mazurov, A., Lippiello, P.M., Bencherif, M., 2010. An alpha7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. J. Pharmacol. Exp. Ther. 332, 173–180. Martin, L.F., Leonard, S., Hall, M.H., Tregellas, J.R., Freedman, R., Olincy, A., 2007. Sensory gating and alpha-7 nicotinic receptor gene allelic variants in schizoaffective disorder, bipolar type. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 611–614. Meyer-Lindenberg, A., Tost, H., 2012. Neural mechanisms of social risk for psychiatric disorders. Nat. Neurosci. 15, 663–668. Meyer-Lindenberg, A., Miletich, R.S., Kohn, P.D., Esposito, G., Carson, R.E., Quarantelli, M., Weinberger, D.R., Berman, K.F., 2002. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat. Neurosci. 5, 267–271. Moskvina, V., Craddock, N., Holmans, P., Nikolov, I., Pahwa, J.S., Green, E., Owen, M.J., O'Donovan, M.C., 2009. Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol. Psychiatry 14, 252–260. Mueller, H.T., Haroutunian, V., Davis, K.L., Meador-Woodruff, J.H., 2004. Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. Brain Res. Mol. Brain Res. 121, 60–69. Murray, R.M., Lewis, S.W., 1987. Is schizophrenia a neurodevelopmental disorder? Br. Med. J. (Clin. Res. Ed) 295, 681–682. Myers, J.M., Martins, G.G., Ostrowski, J., Stachowiak, M.K., 2003. Nuclear trafficking of FGFR1: a role for the transmembrane domain. J. Cell. Biochem. 88, 1273–1291. Newhouse, P., Singh, A., Potter, A., 2004. Nicotine and nicotinic receptor involvement in neuropsychiatric disorders. Curr. Top. Med. Chem. 4, 267–282. O'Donovan, M.C., Norton, N., Williams, H., Peirce, T., Moskvina, V., Nikolov, I., Hamshere, M., Carroll, L., Georgieva, L., Dwyer, S., Holmans, P., Marchini, J.L., Spencer, C.C., Howie, B., Leung, H.T., Giegling, I., Hartmann, A.M., Moller, H.J., Morris, D.W., Shi, Y., Feng, G., Hoffmann, P., Propping, P., Vasilescu, C., Maier, W., Rietschel, M., Zammit, S., Schumacher, J., Quinn, E.M., Schulze, T.G., Iwata, N., Ikeda, M., Darvasi, A., Shifman, S., He, L., Duan, J., Sanders, A.R., Levinson, D.F., Adolfsson, R., Osby, U., Terenius, L., Jonsson, E.G., Cichon, S., Nothen, M.M., Gill, M., Corvin, A.P., Rujescu, D., Gejman, P.V., Kirov, G., Craddock, N., Williams, N.M., Owen, M.J., 2009. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2. Mol. Psychiatry 14, 30–36. Popolo, M., McCarthy, D.M., Bhide, P.G., 2004. Influence of dopamine on precursor cell proliferation and differentiation in the embryonic mouse telencephalon. Dev. Neurosci. 26, 229–244. Postma, P., Gray, J.A., Sharma, T., Geyer, M., Mehrotra, R., Das, M., Zachariah, E., Hines, M., Williams, S.C., Kumari, V., 2006. A behavioural and functional neuroimaging investigation into the effects of nicotine on sensorimotor gating in healthy subjects and persons with schizophrenia. Psychopharmacology (Berl.) 184, 589–599. Potkin, S.G., Macciardi, F., Guffanti, G., Fallon, J.H., Wang, Q., Turner, J.A., Lakatos, A., Miles, M.F., Lander, A., Vawter, M.P., Xie, X., 2010. Identifying gene regulatory networks in schizophrenia. Neuroimage 53, 839–847. Powell, S.B., Zhou, X., Geyer, M.A., 2009. Prepulse inhibition and genetic mouse models of schizophrenia. Behav. Brain Res. 204, 282–294. Poyurovsky, M., Koren, D., Gonopolsky, I., Schneidman, M., Fuchs, C., Weizman, A., Weizman, R., 2003. Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study. Eur. Neuropsychopharmacol. 13, 123–128. Ralph, R.J., Paulus, M.P., Fumagalli, F., Caron, M.G., Geyer, M.A., 2001. Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists. J. Neurosci. 21, 305–313. Rapoport, J.L., Giedd, J.N., Gogtay, N., 2012. Neurodevelopmental model of schizophrenia: update 2012. Mol. Psychiatry 17, 1228–1238. Reuss, B., von Bohlen und Halbach, O., 2003. Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res. 313, 139–157. Riva, M.A., Molteni, R., Bedogni, F., Racagni, G., Fumagalli, F., 2005. Emerging role of the FGF system in psychiatric disorders. Trends Pharmacol. Sci. 26, 228–231. Rodriguez-Murillo, L., Gogos, J.A., Karayiorgou, M., 2012. The genetic architecture of schizophrenia: new mutations and emerging paradigms. Annu. Rev. Med. 63, 63–80. Rodriguez-Pallares, J., Guerra, M.J., Labandeira-Garcia, J.L., 2003. Elimination of serotonergic cells induces a marked increase in generation of dopaminergic neurons from mesencephalic precursors. Eur. J. Neurosci. 18, 2166–2174. Schmidt, C.J., Kehne, J.H., Carr, A.A., Fadayel, G.M., Humphreys, T.M., Kettler, H.J., McCloskey, T.C., Padich, R.A., Taylor, V.L., Sorensen, S.M., 1993. Contribution of serotonin neurotoxins to understanding psychiatric disorders: the role of 5-HT2 receptors in schizophrenia and antipsychotic activity. Int. Clin. Psychopharmacol. 8 (Suppl. 2), 25–32. Schultz, W., 2002. Getting formal with dopamine and reward. Neuron 36, 241–263. Shao, L., Vawter, M.P., 2008. Shared gene expression alterations in schizophrenia and bipolar disorder. Biol. Psychiatry 64, 89–97. Simpson, E.H., Kellendonk, C., Kandel, E., 2010. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 65, 585–596. Stachowiak, M.K., 2012. A novel nuclear FGF receptor-1 partnership with retinoid and Nur receptors in neuronal programming of embryonic stem cells . (New York, NY). Stachowiak, M.K., Bruno, J.P., Snyder, A.M., Stricker, E.M., Zigmond, M.J., 1984. Apparent sprouting of striatal serotonergic terminals after dopamine-depleting brain lesions in neonatal rats. Brain Res. 291, 164–167. Stachowiak, M.K., Maher, P.A., Joy, A., Mordechai, E., Stachowiak, E.K., 1996. Nuclear accumulation of fibroblast growth factor receptors is regulated by multiple signals in adrenal medullary cells. Mol. Biol. Cell 7, 1299–1317.

376

M.K. Stachowiak et al. / Schizophrenia Research 143 (2013) 367–376

Stachowiak, M.K., Fang, X., Myers, J.M., Dunham, S.M., Berezney, R., Maher, P.A., Stachowiak, E.K., 2003. Integrative nuclear FGFR1 signaling (INFS) as a part of a universal “feed-forward-and-gate” signaling module that controls cell growth and differentiation. J. Cell. Biochem. 90, 662–691. Stachowiak, M.K., Maher, P.A., Stachowiak, E.K., 2007a. Integrative nuclear signaling in cell development — a role for FGF receptor-1. DNA Cell Biol. 26, 811–826. Stachowiak, M.K., Maher, P.A., Stachowiak, E.K., 2007b. Integrative nuclear signaling in cell development — a role for FGF receptor-1. DNA Cell Biol. 26, 811–826. Stachowiak, E.K., Roy, I., Lee, Y.W., Capacchietti, M., Aletta, J.M., Prasad, P.N., Stachowiak, M.K., 2009. Targeting novel integrative nuclear FGFR1 signaling by nanoparticle-mediated gene transfer stimulates neurogenesis in the adult brain. Integr. Biol. (Camb.) 1, 394–403. Stachowiak, M.K., Stachowiak, E.K., Aletta, J.M., Tzanakakis, E.S., 2011. A common integrative nuclear signaling module for stem cell development. In: Stachowiak, E.S.T.M.K. (Ed.), Stem Cells from Mechanisms to Technologies. World Scientific, pp. 87–132. Stolerman, I.P., Mirza, N.R., Hahn, B., Shoaib, M., 2000. Nicotine in an animal model of attention. Eur. J. Pharmacol. 393, 147–154. Suemaru, K., Yasuda, K., Umeda, K., Araki, H., Shibata, K., Choshi, T., Hibino, S., Gomita, Y., 2004. Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic alpha7 receptors. Br. J. Pharmacol. 142, 843–850. Sun, J., Jia, P., Fanous, A.H., van den Oord, E., Chen, X., Riley, B.P., Amdur, R.L., Kendler, K.S., Zhao, Z., 2010. Schizophrenia gene networks and pathways and their applications for novel candidate gene selection. PLoS One 5, e11351. Swerdlow, N.R., Taaid, N., Oostwegel, J.L., Randolph, E., Geyer, M.A., 1998. Towards a crossspecies pharmacology of sensorimotor gating: effects of amantadine, bromocriptine, pergolide and ropinirole on prepulse inhibition of acoustic startle in rats. Behav. Pharmacol. 9, 389–396. Swerdlow, N.R., Weber, M., Qu, Y., Light, G.A., Braff, D.L., 2008. Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl.) 199, 331–388. Terwisscha van Scheltinga, A.F., Bakker, S.C., Kahn, R.S., 2010. Fibroblast growth factors in schizophrenia. Schizophr. Bull. 36, 1157–1166. Thompson, J.L., Pogue-Geile, M.F., Grace, A.A., 2004. Developmental pathology, dopamine, and stress: a model for the age of onset of schizophrenia symptoms. Schizophr. Bull. 30, 875–900. Tidey, J.W., Rohsenow, D.J., Kaplan, G.B., Swift, R.M., 2005. Cigarette smoking topography in smokers with schizophrenia and matched non-psychiatric controls. Drug Alcohol Depend. 80, 259–265. Tietje, K.R., Anderson, D.J., Bitner, R.S., Blomme, E.A., Brackemeyer, P.J., Briggs, C.A., Browman, K.E., Bury, D., Curzon, P., Drescher, K.U., Frost, J.M., Fryer, R.M., Fox, G.B., Gronlien, J.H., Hakerud, M., Gubbins, E.J., Halm, S., Harris, R., Helfrich, R.J., Kohlhaas, K.L., Law, D., Malysz, J., Marsh, K.C., Martin, R.L., Meyer, M.D., Molesky, A.L., Nikkel, A.L., Otte, S., Pan, L., Puttfarcken, P.S., Radek, R.J., Robb, H.M., Spies, E., Thorin-Hagene, K., Waring, J.F., Ween, H., Xu, H., Gopalakrishnan, M., Bunnelle, W.H., 2008. Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties. CNS Neurosci. Ther. 14, 65–82. Toru, M., Nishikawa, T., Mataga, N., Takashima, M., 1982. Dopamine metabolism increases in post-mortem schizophrenic basal ganglia. J. Neural Transm. 54, 181–191.

Trokovic, R., Trokovic, N., Hernesniemi, S., Pirvola, U., Vogt Weisenhorn, D.M., Rossant, J., McMahon, A.P., Wurst, W., Partanen, J., 2003. FGFR1 is independently required in both developing mid- and hindbrain for sustained response to isthmic signals. EMBO J. 22, 1811–1823. Trokovic, R., Jukkola, T., Saarimaki, J., Peltopuro, P., Naserke, T., Weisenhorn, D.M., Trokovic, N., Wurst, W., Partanen, J., 2005. Fgfr1-dependent boundary cells between developing mid- and hindbrain. Dev. Biol. 278, 428–439. Turner, C.A., Akil, H., Watson, S.J., Evans, S.J., 2006. The fibroblast growth factor system and mood disorders. Biol. Psychiatry 59, 1128–1135. Turner, C.A., Calvo, N., Frost, D.O., Akil, H., Watson, S.J., 2008. The fibroblast growth factor system is downregulated following social defeat. Neurosci. Lett. 430, 147–150. Vagenakis, G.A., Hyphantis, T.N., Papageorgiou, C., Protonatariou, A., Sgourou, A., Dimopoulos, P.A., Mavreas, V., Vagenakis, A.G., Georgopoulos, N.A., 2004. Kallmann's syndrome and schizophrenia. Int. J. Psychiatry Med. 34, 379–390. van der Kooy, D., Hattori, T., 1980. Dorsal raphe cells with collateral projections to the caudate–putamen and substantia nigra: a fluorescent retrograde double labeling study in the rat. Brain Res. 186, 1–7. Wallace, T.L., Callahan, P.M., Tehim, A., Bertrand, D., Tombaugh, G., Wang, S., Xie, W., Rowe, W.B., Ong, V., Graham, E., Terry Jr., A.V., Rodefer, J.S., Herbert, B., Murray, M., Porter, R., Santarelli, L., Lowe, D.A., 2011. RG3487, a novel nicotinic alpha7 receptor partial agonist, improves cognition and sensorimotor gating in rodents. J. Pharmacol. Exp. Ther. 336, 242–253. Williams, E.J., Walsh, F.S., Doherty, P., 2003. The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J. Cell Biol. 160, 481–486. Williams, J.M., Gandhi, K.K., Lu, S.E., Kumar, S., Shen, J., Foulds, J., Kipen, H., Benowitz, N.L., 2010. Higher nicotine levels in schizophrenia compared with controls after smoking a single cigarette. Nicotine Tob. Res. 12, 855–859. Winterer, G., 2010. Why do patients with schizophrenia smoke? Curr. Opin. Psychiatry 23, 112–119. Wong, A.H., Van Tol, H.H., 2003. Schizophrenia: from phenomenology to neurobiology. Neurosci. Biobehav. Rev. 27, 269–306. Wong, J., Woon, H.G., Weickert, C.S., 2011. Full length TrkB potentiates estrogen receptor alpha mediated transcription suggesting convergence of susceptibility pathways in schizophrenia. Mol. Cell. Neurosci. 46, 67–78. Woznica, A.A., Sacco, K.A., George, T.P., 2009. Prepulse inhibition deficits in schizophrenia are modified by smoking status. Schizophr. Res. 112, 86–90. Yi Yang, R.C., Becker, Chani, Terranova, Christopher, Stachowiak, Michal K., Wersinger, Scott R., 2010. Impaired Performance on an Object Recognition Task Suggests a Working Memory Deficit in a Mouse Model of Schizophrenia. Society for Neuroscience, San Diego, CA. Zheng, C., Shen, Y., Xu, Q., 2012. Association of intron 1 variants of the dopamine transporter gene with schizophrenia. Neurosci. Lett. 513, 137–140. Zhong, K.X., Sweitzer, D.E., Hamer, R.M., Lieberman, J.A., 2006. Comparison of quetiapine and risperidone in the treatment of schizophrenia: a randomized, double-blind, flexible-dose, 8-week study. J. Clin. Psychiatry 67, 1093–1103. Zigmond, M.J., Acheson, A.L., Stachowiak, M.K., Stricker, E.M., 1984. Neurochemical compensation after nigrostriatal bundle injury in an animal model of preclinical parkinsonism. Arch. Neurol. 41, 856–861.