Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis

Neuropharmacology xxx (2013) 1e11

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Invited review

Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis Valentina Wiescholleck, Denise Manahan-Vaughan* Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Universitätsstr. 150, MA 4/150, 44780 Bochum, Germany

a r t i c l e i n f o

a b s t r a c t

Article history: Received 16 November 2012 Received in revised form 21 December 2012 Accepted 4 January 2013

It is postulated that disruptions of glutamatergic signalling may underlie the pathophysiology of psychosis and schizophrenia. A strong body of evidence indicates that antagonism of the N-methyl-Daspartate receptor (NMDAR) leads to similar molecular, cellular, cognitive and behavioural changes in rodents and/or humans to those that have been identified to occur in psychosis. One of the main loci of change appears to comprise the hippocampus, raising the question as to whether changes in hippocampal glutamatergic transmission may drive changes in GABAergic and dopaminergic-mediated signalling in schizophreniform diseases. NMDAR antagonists such as MK801, PCP and ketamine all elicit similar psychosis-related effects, with MK801 inducing the most potent psychotomimetic reactions. Treatment with MK801 is associated with a loss of hippocampal synaptic plasticity, hippocampusdependent learning and cognitive deficits. These findings have raised the question as to whether targeting the NMDA receptors or its modulators could prove an effective strategy in treatment of psychosis and schizophrenia. Specifically, the otherwise untreatable negative and cognitive symptoms of schizophrenia currently comprise the highest research priority. A single injection with MK801 has been used to emulate first-episode psychosis in animals. This treatment induces both psychosis-related acute effects but interestingly also persisting consequences, which might be more sensitive as indicators of drug efficacy. Here, we review the current status of the field with regard to the MK801 animal model of firstepisode psychosis and its relevance for the glutamate hypothesis of schizophrenia. Furthermore, we argue that synaptic plasticity may be a better assay for assessing novel schizophrenia therapeutics than behavioural evaluation. This article is part of a Special Issue entitled ‘GluR-dep synaptic plasticity’. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Schizophrenia Psychosis Animal model MK801 LTP Hippocampus Dizocilpine

1. Introduction Schizophrenia is a complex chronic psychiatric disorder that affects 1% of the human population worldwide. Becoming manifest already in late adolescence or early adulthood, it is associated with lifelong disability for the suffering individual, and its therapy is associated with enormous costs to society (Lindsley et al., 2006). Schizophrenia has therefore been described as a “leading public health challenge” (Carpenter and Koenig, 2008). Typically, it is characterized by positive (delusions, hallucinations and thought disorder) and negative (avolition, alogia and affective flattening) symptoms, that are accompanied by cognitive deficits (memory and attention dysfunction) (Harrison, 1999). Although the prime diagnostic criteria for schizophrenia rely mainly on the more obvious positive symptoms, the significance of the previously * Corresponding author. Tel.: þ49 234 3222042; fax: þ49 234 3214192. E-mail address: [email protected] (D. Manahan-Vaughan).

rather under-recognized cognitive deficits has recently come more and more to the fore of schizophrenia research (Insel, 2010). It is now clear that impaired cognition may be central in schizophrenia pathology and that it is strongly associated with schizophreniarelated long-term disability (Insel, 2010; Carpenter and Koenig, 2008; Stone and Hsi, 2011). More than 50 years after the discovery of the dopamine D2-receptor antagonist, chlorpromazine, almost all currently available antipsychotics still target D2receptors (Kapur and Mamo, 2003). Such antipsychotics usually treat the positive, but not negative or cognitive symptoms of psychosis (Carpenter and Koenig, 2008), which is considered by patients as being very burdensome. Moreover, although a combination of antipsychotic medication and psychosocial therapy initially improves acute psychotic symptoms in some patients, relapse rates comprise approximately 80% (Robinson et al., 2004). Hence, the course of the disease is almost always chronic, and usually characterised by alternating phases of remission and exacerbation. Available therapies treat the symptoms and not the

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Please cite this article in press as: Wiescholleck, V., Manahan-Vaughan, D., Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.01.001

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disease itself, and are often rejected by sufferers due to severe sideeffects (Tamminga, 2009). 2. The NMDAR-hypofunction hypothesis Several different hypotheses that aim to explain the pathophysiology of schizophrenia have emerged. Before the NMDA (Nmethyl-D-aspartate) receptor (NMDAR) hypofunction hypothesis of schizophrenia evolved approximately 30 years ago, the dopamine hyperactivity hypothesis was predominant in the schizophrenia research field. This hypothesis was mainly based on two observations: firstly, at that time, the effective antipsychotics were all dopamine receptor antagonists (van Rossum, 1966). Secondly, amphetamines (dopamine-enhancing psychostimulants) were shown to produce psychotic symptoms in humans (Angrist et al., 1974; Lieberman et al., 1987). Hence, an overdrive of the dopaminergic system, specifically at striatal D2-receptors, was postulated to underlie schizophrenia pathology (Seeman, 1987). Up until current times, the dopamine hypothesis is still used to explain psychotic aspects of schizophrenia. However, it has become progressively clear that dopamine dysfunction does not entirely explain the whole complexity of the disease, and particularly of the cognitive and negative symptoms. In 1980, it was discovered that glutamate is reduced in the cerebrospinal fluid of schizophrenic patients (Kim et al., 1980), indicating that this major excitatory neurotransmitter might be also involved in schizophrenia pathology. Later, it was discovered that phencyclidine (PCP, today a common drug of abuse, known as “angel dust”) and ketamine (an anesthetic), both act as noncompetitive irreversible NMDAR antagonists and induce positive, negative and cognitive symptoms of schizophrenia in healthy subjects (Javitt and Zukin, 1991; Krystal et al., 1994). The psychotomimetic effects of PCP have therefore been referred to as the “best available phenocopy of schizophrenic psychosis” (Kornhuber and Weller, 1997). Furthermore, all kinds of symptoms in schizophrenic patients were exacerbated by the non-competitive irreversible NMDAR antagonist ketamine at subanesthetic doses (Lahti et al., 2001). On the basis of these findings, the so-called NMDARhypofunction hypothesis was formulated. NMDARs play an important role in synaptic plasticity, as well as in learning and memory (Tsien et al., 1996; Chen et al., 2009). In order to be activated, two events have to coincide: binding of the ligand (glutamate) and of a co-agonist (glycine), as well as release of the Mg2þ block of the ion channel by strong depolarization of the postsynaptic membrane (Mori and Mishina, 1995). Thus, the NMDAR is unique in its function as coincidence detector for presynaptic and postsynaptic activity (Fig. 1). A convincing body of evidence supports the idea that a disturbance in NMDAR functioning is critically involved in schizophrenia pathology (Moghaddam, 2003; Lindsley et al., 2006). For instance, mRNA levels of NMDAR GluN1 and GluN2B subunits are altered in post-mortem hippocampal tissue of schizophrenic patients (Gao et al., 2000). Moreover, the majority of risk genes for schizophrenia, identified by genetic linkage and association studies, are related to NMDAR-functioning (Moghaddam, 2003). Finally, an imaging study, using a highly selective single photon emission tomography (SPET) NMDAR tracer, has provided first in-vivo evidence of an NMDAR deficit in schizophrenic patients (Pilowsky et al., 2006). Just recently, reduced GluN1 (mRNA and protein) and GluN2C (mRNA) expression has been detected in the largest postmortem cohort of schizophrenic patients to date (Weickert et al., 2012). Theoretically, the NMDAR-hypofunction hypothesis provides the unique possibility to integrate nearly all distinct pieces of evidence from schizophrenia research regarding the involvement of

Fig. 1. Schematic representation and binding sites of the NMDAR. The NMDAR is an ionotropic glutamate receptor. It forms hetero-tetramers between two obligatory GluN1 subunits and two GluN2 or GluN3 subunits. In order to be activated, ligand binding, as well as membrane depolarization, are needed.

different neurotransmitter systems. The link to the dopamine hypothesis is demonstrated by the finding that dopamine receptor expression is altered in rats after treatment with the irreversible NMDAR-antagonist MK801 (Healy and Meador-Woodruff, 1996). Moreover, dopaminergic neurons increase their firing rates upon intravenous treatment with MK801 (Zhang et al., 1992). Hence, an NMDAR-deficiency might give rise to the secondary dopamine dysfunction in schizophrenia. In addition, findings related to the cannabinoid system can be integrated into the NMDAR-hypofunction hypothesis. Cannabisabuse in adolescence increases the risk for schizophrenia (Malone et al., 2010). Interestingly, activation of presynaptic cannabinoid CB1 receptors reduces glutamate release in various brain areas (Lévénés et al., 1998; Shen et al., 1996; Gerdeman and Lovinger, 2001). Less glutamate in the synapse causes consequently less activation of postsynaptic NMDARs, producing an NMDARhypofunction. Finally, the inhibitory GABAergic system has been suggested to be substantially involved in schizophrenia pathology. Lowered levels of cortical GABA were found in brains of schizophrenic patients (Perry et al., 1979). In line with this, post-mortem studies revealed that mRNA for glutamate decarboxylase GAD67 (enzyme responsible for GABA synthesis) is reduced in schizophrenia (Akbarian and Huang, 2006). There is also a decrease of parvalbumin (Ca2þ e binding protein) e containing neurons in the hippocampus of schizophrenics (Zhang et al., 2002). Thus, schizophrenia pathology is associated with a deficit in GABA synthesis and release, particularly in parvalbumin-containing basket and chandelier interneurons. Interestingly, treatment with uncompetitive irreversible NMDAR antagonists causes a reduction in GAD67 and parvalbumin specifically in parvalbumin-containing interneurons

Please cite this article in press as: Wiescholleck, V., Manahan-Vaughan, D., Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.01.001

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in cell culture (Kinney et al., 2006) and a general decrease in parvalbumin mRNA in certain brain areas in-vivo (Cochran et al., 2003), closely resembling the findings of post-mortem studies in schizophrenic patients (Hashimoto et al., 2003). These findings led to a readjustment of the original NMDAR-hypofunction hypothesis, which now assumes that specifically the NMDARs of GABAergic parvalbumin-containing fast-spiking interneurons are central to schizophrenia pathology (Bitanihirwe et al., 2009; Belforte et al., 2010). Under control conditions, the main function of the local inhibitory interneurons network is to monitor and to balance the level of pyramidal cells excitation by releasing GABA (Gordon, 2010) (Fig. 2A). It has been proposed that interneurons use their NMDARs to sense pyramidal cell activity (Lisman et al., 2008). Consequently, a hypofunction of NMDARs in interneurons would mimic insufficient excitation and cause reduced release of GABA, thereby producing a disinhibition of pyramidal cells (Fig. 2B). In line with this, an interneuron-specific partial (up to about 50%) reduction in GluN1 subunits in cortical and hippocampal inhibitory interneurons in an animal model leads to a schizophrenia-related behavioural profile, including prepulse inhibition disruption and deficits in spatial working memory (Belforte et al., 2010). Thus, neither the DA-hypothesis, the GABA hypothesis nor the NMDAR hypothesis are mutually exclusive. It is in fact very likely that all three systems undergo disruptions that contribute to the pathophysiology of schizophrenia/psychosis. The abovementioned data suggest, however, that changes in NMDAR function and/or signalling may be at the centre of these alterations.

2.1. Use of animal models in psychiatric research The use of animal models in neuroscientific research is of irreplaceable value. Besides being an important tool for understanding pathological mechanisms, animal models are also necessary for testing hypotheses that cannot be addressed in human studies and for developing and preclinical testing of new treatment approaches. However, investigating psychiatric illnesses in animals is quite difficult, as these illnesses are characterized by disturbances in

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functions assigned to humans only e e.g. hallucinations, delusions and thought disorders. That is why no animal model is able to fully mimic a complex psychiatric disease. Nevertheless, certain aspects of psychiatric disorders can indeed be modelled and studied in animals. Specifically, in schizophrenia research, genetic (Sibley, 1999; Mohn et al., 1999; Gray et al., 2009) and pharmacological models (Jentsch and Roth, 1999; Corlett et al., 2011) are widely used in order to investigate the impact of certain candidate genes or of certain receptors and neurotransmitter systems on schizophreniarelated behaviour and endophenotypes. Furthermore, although certain schizophrenia-relevant behavioural aspects are absolutely unique to humans, some can indeed be modelled and quite objectively assessed in rodents. For instance, prepulse inhibition (a weak pre-stimulus reduces the response to a subsequent strong stimulus), reflecting sensory gating abilities, is disrupted in schizophrenic patients and in animals treated with psychotomimetic compounds (Geyer et al., 2001). Furthermore, social interaction behaviour can be assessed in humans (Bellack et al., 1990), as well as in highly social rodents (Sams-Dodd, 1999). Finally, nonverbal memoryrelated tasks are easily performable in humans as well as in animals (Goulart et al., 2010; Conrad, 2010; Dudchenko, 2004; Bussey et al., 2012; Schretlen et al., 2007; Fouquet et al., 2010). Moreover, molecular changes in post-mortem tissue of schizophrenic patients can be compared to those in animals displaying a schizophreniarelated behavioural profile, which in addition exclude the biases of personal history and treatment thereby allowing us to identify new targets for potential therapeutics. All in all, if certain questions cannot be studied in humans due to ethical concerns, animal models comprise a useful tool to test schizophrenia-relevant hypotheses in a causal rather than correlational way.

2.2. Modelling NMDAR-dysfunction with MK801 The uncompetitive irreversible NMDAR antagonist, MK801((þ)5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), also known as dizocilpine, was developed by the Merck Institute for Therapeutic Research and first described in an official

Fig. 2. NMDAR-hypofunction hypothesis of schizophrenia pathology and plasticity disruption. (A) Inhibitory interneurons sense levels of excitatory activity of the principle cell via NMDAR signalling and release GABA onto the principle cell as a consequence. Under normal circumstances this serves to keep neuronal excitability and basal tonus within a functional range. Under circumstances where patterned afferent activation occurs, glutamate is released from the principle cell and LTP is triggered at the postsynapse of e.g. hippocampal CA1 or dentate gyrus synapses by activation of NMDARs. (B) In schizophrenia, decreased NMDAR signalling misleads the inhibitory interneurons into acting as if there is insufficient excitatory activity. Therefore, inhibitory interneurons down-regulate their output and disinhibit excitatory neurons. An increased basal excitability tonus can be anticipated, that results in enhanced basal glutamatergic transmission, and reduces the possible range for synaptic potentiation. In addition, loss of NMDARs or loss of NMDAR function at the postsynapse leads to decreased postsynaptic depolarisation during patterned afferent activity, and as a result LTP is impaired.

Please cite this article in press as: Wiescholleck, V., Manahan-Vaughan, D., Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.01.001

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research paper in 1982 (Clineschmidt et al., 1982). Being highly selective and potent as well as easily crossing the blood brain barrier, MK801 was supposed to prevent brain damage related to glutamate excitotoxicity. Originally, it was invented as a new anticonvulsant (Clineschmidt et al., 1982). Later, it was assessed as a potential pharmacological intervention in asphyxia and stroke research (Gunn et al., 1988; Kochhar et al., 1988). Since the 1990s, MK801 has been implemented more and more in schizophrenia research, mainly based on the psychotomimetic properties of uncompetitive NMDAR antagonists, ketamine and PCP, that were discovered at around this time (Javitt and Zukin, 1991; Krystal et al., 1994). Nowadays, MK801 is frequently used in animal research on psychosis in order to model schizophrenia or acute psychosis after chronic or single administration, respectively (Rujescu et al., 2006; Eyjolfsson et al., 2006; Adell et al., 2012; Manahan-Vaughan et al., 2008a; Wiescholleck and Manahan-Vaughan, 2012a,b). 2.3. The uniqueness of MK801-kinetics MK801 binds to the PCP binding site within the NMDAR channel pore and thus prevents ion flow. The highest density of MK801binding sites occurs in the hippocampus (Wong et al., 1986). Maximal brain concentration following a systemic injection in rats is reached within 30 min and the elimination half-life time of free diffusible MK801 is approximately 2 h (Vezzani et al., 1989). What makes MK801 so unique among other NMDAR antagonists is its special binding kinetics. First of all, MK801 is characterized by its extremely high binding affinity (10-fold higher than that of PCP and more than 100 times higher than that of ketamine) (Kornhuber and Weller, 1997) with estimated Ki values in a range of 2e15 nM (MacDonald et al., 1991). In addition, MK801 is characterized by its extraordinarily high selectivity for the PCP site in contrast to other PCP site ligands (Wong et al., 1986). Moreover, even very high doses of MK801 show no effect on responses to quisqualate or kainate (Wong et al., 1986). Interestingly, affinity to the PCP binding site is strongly correlated to the psychotomimetic potential of uncompetitive NMDAR antagonists with MK801 displaying the strongest binding potency and therefore highest potential to induce psychotomimetic behaviour (Kornhuber and Weller, 1997). Secondly, physiological activation of the channel appears necessary in order to make the PCP site accessible to MK801 (Huettner and Bean, 1988). That is why MK801 is often described as “use-dependent open-channel blocker”. In line with this, MK801binding is increased in the presence of endogenous and exogeneous NMDAR agonists (Foster and Wong, 1987). There is, however, also evidence indicating that MK801 does not exclusively, though preferentially, bind in the open channel state. Based on their study of [3H]MK-801- binding under various degrees of NMDAR receptor activation, Javitt and Zukin (1989), concluded that MK801 binds to closed as well as to open conformations of the NMDAR with lowaffinity (Kd ¼ 34  4 nM) and high-affinity (Kd ¼ 0.8  0.4 nM) binding kinetics respectively (Javitt and Zukin, 1989). Thirdly, the dissociation rate of MK801 under physiological conditions (70 mV) is extremely low with an at least ten times slower reverse rate constant than that of PCP (MacDonald et al., 1991). In line with this, the reverse rate has been identified as the major factor that accounts for differences in relative potency among ketamine, PCP and MK801 (the forward rate constants are similar for all three substances) (MacDonald et al., 1991). Due to this remarkably slow dissociation rate, MK801 has even been described as “irreversible” in the literature (Rosenmund et al., 1993; Dzubay and Jahr, 1996; Talukder et al., 2010). This description goes back to in vitro studies, in which MK801-blockade could not be reversed by a washout of the substance within the time frame of an in vitro experiment (min to hours) (Rosenmund et al., 1993; Huettner and

Bean, 1988; Halliwell et al., 1989). Evidence exists that the recovery (but not the onset) of the MK801-blockade is voltagedependent (Huettner and Bean, 1988). Strong membrane depolarization during washout accelerates the recovery from MK801block in patch-clamp experiments (Huettner and Bean, 1988; Halliwell et al., 1989). It is however, questionable, if physiological activation ever causes persistent increase of the membrane potential of that magnitude lasting for such a long period as under voltage clamp conditions (holding potential of þ30 mV or þ40 mV for several seconds to minutes). In addition, the dissociation rate seems to depend on the concentration of MK801. If extremely high concentrations of MK801 are used (hundreds or thousands of times of the Ki value), the block will be substantial at any membrane potential (MacDonald et al., 1991). Taking all these pharmacological facts into account, the mechanism of action of MK801 can be interpreted in a more precise way. MK801 will, on the one hand, bind with high-affinity to NMDAR channels that are in the activated open-state at synapses being currently used and block them. On the other hand it will bind with low-affinity to inactivated closed channels. Estimated deactivation time constants of NMDARs are approx. 200 ms and 1e3 s (Andersen et al., 2007). Displaying very slow dissociation kinetics, a certain amount of MK801 will be trapped within the channel pore after unbinding of ligands and closing of the NMDARs. In these channels MK801-block will probably persist until recycling of the receptor (turn-over rate for surface NMDARs is supposed to happen with a half-life time of approximately 16  5 h (Huh and Wenthold, 1999)). Thus, these channels will indeed essentially be blocked in an irreversible manner. 2.4. The MK801 animal model of first-episode psychosis The first detectable symptoms of schizophrenia usually occur at a peak age of between 18 and 25 years. This is referred to as firstepisode psychosis (Gleeson et al., 2010). If not treated effectively within a certain time window, first-episode psychosis may progress into chronic schizophrenic illness (Alvarez-Jimenez et al., 2011). Therefore, first-episode psychosis plays a crucial role in processes leading to the development of chronic schizophrenia. This has raised substantial interest in identifying strategies to intervene immediately after first-episode psychosis and therefore possibly halt the progress of the disease. In the MK801 model of first-episode psychosis, a single injection of MK801, an irreversible uncompetitive NMDAR-antagonist, is applied systemically to rats (Wöhrl et al., 2007; Kehrer et al., 2007; Manahan-Vaughan et al., 2008a,b; Wiescholleck and ManahanVaughan, 2012a,b). Different quality criteria have been introduced in order to score an animal model’s ability to generate data that is relevant to the modelled clinical condition and to thus validate the model (van der Staay, 2006). For evaluation reasons, three main validation criteria have been proposed for animal models: predictive validity (prediction of human performance), construct validity (theoretical rationale of the model) and face validity (symptoms similarity) (Lipska and Weinberger, 2000; Marcotte et al., 2001). As MK801 binds within the channel pore at the PCP binding site (Fig. 1) and blocks the NMDAR, this pharmacological model is consistent with the NMDAR-hypofunction hypothesis and fulfills therefore the criterion of construct validity. The fact that the same substance that reliably induces psychosis in humans is applied to animals, and that irreversible uncompetitive NMDAR antagonists induce psychotic symptoms in healthy humans and exacerbate symptoms of schizophrenic patients (Lahti et al., 2001; Krystal et al., 1994) supports the predictive validity of the model. Moreover, certain psychosisrelated MK801-induced behaviours can be antagonized by clinically used antipsychotics (Mutlu et al., 2011). The criterion of face

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validity is generally fairly difficult to fulfil in rodents. However, some aspects (e.g. deficit in prepulse inhibition and disrupted memory) clearly occur in both, psychotic patients (Gold and Harvey, 1993; Braff and Geyer, 1990) and MK801-treated animals (Manahan-Vaughan et al., 2008a; Wiescholleck and ManahanVaughan, 2012a), thereby supporting the face validity of the model. 2.5. The MK801 animal model of first-episode psychosis e acute effects Compared to ketamine and PCP, a single treatment with MK801 induces all kinds of acute schizophrenia-related symptoms in animals (Table 1). We refer to effects as “acute” or “short-term” if the testing took place hours to maximally 4 days after treatment with MK801. Hyperlocomotion and stereotypy are robust acute consequences of a single MK801-treatment that are supposed to reflect positive symptoms-like behaviour in rodents (Benvenga and Spaulding, 1988; Heale and Harley, 1990; Tiedtke et al., 1990; Hoffman, 1992; Dai et al., 1995; Wöhrl et al., 2007; ManahanVaughan et al., 2008a). Furthermore, negative symptoms-related behaviour is mirrored by a decrease in social interaction directly after a single application of MK801 (Rung et al., 2005; Zou et al., 2008). On the one hand, sensorimotor deficits are demonstrated by acute disturbance of prepulse inhibition after a single MK801treatment (Manahan-Vaughan et al., 2008a). On the other hand, MK801 induces hippocampus- and prefrontal cortex (PFC)dependent memory deficits in diverse standard rodent memory tasks, including the passive avoidance task, spatial delayed alternation task, spontaneous alternation task, Morris water maze, conditional Y-maze task (Benvenga and Spaulding, 1988; Jones et al., 1990; Verma and Moghaddam, 1996; Fraser et al., 1997; Heale and Harley, 1990; Murray and Ridley, 1997). Due to this profound memory-impairing effect, MK801 has been referred to as a “cognition impairer” (van der Staay et al., 2011). Besides these reliable behavioural consequences, a single treatment with MK801 induces acute molecular disturbances that are, at least partly, comparable to those in schizophrenia, including a decrease in parvalbumin mRNA (Romón et al., 2011), an increase in extracellular dopamine levels (Wedzony et al., 1993) and an increase in dopamine receptor expression (Wedzony et al., 1993, 1996). The picture of acute consequences of a single MK801-treatment is completed by electrophysiological changes, such as increased hippocampus-mediated spontaneous firing in the medial prefrontal cortex (mPFC) (Jodo et al., 2005) and a deficit in the ability to induce hippocampal LTP in vitro (Coan et al., 1987) and in-vivo (Abraham and Mason, 1988). In area CA1 and dentate gyrus of the hippocampal formation acute MK801-treatment increases gamma power oscillations (Kittelberger et al., 2012). Moreover, in hippocampal slices of animals pretreated with MK801, the kainate-induced gamma frequency field oscillation power in area CA1 is increased (Kehrer et al., 2007). Finally, a single application of MK801 increases neuronal activity in the hippocampus, other limbic cortical regions, the thalamus and nucleus accumbens as demonstrated by 2-DG uptake after a single injection of MK801 (Duncan et al., 1999). 2.6. The MK801 animal model of first-episode psychosis e longlasting effects on plasticity and spatial memory Interestingly, the concept of synaptic plasticity has been linked to schizophrenia pathology in many contemporary theoretical considerations (Peled, 2005; McGlashan, 2006). A fascinating, though yet rather underestimated, property of MK801 is its ability to induce long-lasting or even persistent effects on synaptic plasticity and memory in rodents (Table 2). Already in 1996, Wozniak et al. reported long-lasting impairment in a spatial learning task

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after a single MK801-treatment (10 mg/kg s.c.) which persisted for at least 5 months (Wozniak et al., 1996). More recently, Lukoyanov and Paula-Barbosa (2000) confirmed this result, demonstrating that a single MK801-injection (10 mg/kg i.p.) leads to impairment in the water maze performance lasting for at least 10 weeks. Other more recent studies demonstrated that a single injection of MK801 (5 mg/kg, i.p.) in rats results in short-lasting transient behavioural aspects of psychosis-related behaviour, that are followed by longterm impairments in spatial memory (Manahan-Vaughan et al., 2008a,b; Wiescholleck and Manahan-Vaughan, 2012a,b). A reference memory deficit in the radial maze persisted for at least 4 weeks (Manahan-Vaughan et al., 2008a,b) and object recognition memory was also chronically impaired (Wiescholleck and Manahan-Vaughan, 2012a). In parallel with the long-lasting memory deficits, same treatment induced persistent deficits on synaptic level, as long-term potentiation (LTP) was chronically disrupted at the perforant path-dentate gyrus synapse of the hippocampus in freely moving rats (Manahan-Vaughan et al., 2008a,b; Wiescholleck and Manahan-Vaughan, 2012a,b). LTP impairments have been followed for weeks after a single injection of MK801 (Wiescholleck and Manahan-Vaughan, 2012b). Interestingly, the sensorimotor gating impairment, that was evident 1 d after a single MK801-treatment, was not present 7 and 28 d after a single application of MK801 (Manahan-Vaughan et al., 2008a). One week after a single MK801-treatment, locomotor activity and anxiety-related behaviour, as indicated by total distance moved and percentage of time spent in the centre of an open field arena, respectively, are no longer altered (Wiescholleck and Manahan-Vaughan, 2012a,b). This finding is in line with the study of Wozniak et al., in which no long-lasting effect on locomotion could be detected 9 days after treatment with MK801 (Wozniak et al., 1996). Comparably, Sams-Dodd failed to detect any long-term changes in travelled distance 21 days after MK801 administration (Sams-Dodd, 2004). In addition, he failed to find any enduring deficits in social interaction after MK801-treatment (Sams-Dodd, 2004). Thus, in the long-term perspective MK801-induced NMDARantagonism seems to selectively model persistent schizophreniarelated memory deficits, while other behavioural aspects remain unaffected. Interestingly, cognitive pathology is also supposed to account mainly for the poor long-term functional outcome in schizophrenic patients (Green, 1996; Insel, 2010). Moreover, schizophreniarelated cognitive deficits are as yet untreatable and comprise currently the most urgent research priority. 2.7. MK801 might act in a cell type-specific manner Another interesting point that should be taken into account is the assumption that principle cells and interneurons might respond differently to NMDAR-antagonism. Hippocampal inhibitory LTP in the area CA1, produced by alvear stimulation, has been shown to be more sensitive to NMDAR-antagonism as compared to excitatory LTP produced by Schaffer collateral stimulation (Grunze et al., 1996). The underlying mechanisms of this increased interneuronal affinity for NMDAR-antagonism as compared to principle cells might be diverse. As the NMDAR function in interneurons differs from that in principle cells (as a constant sensor of excitatory neurotransmitter release versus induction of synaptic plasticity), both cell populations will be probably active at slightly distinct times. This will lead to cell type-specific binding of MK801 to openstate NMDARs receptors. Generally, interneurons have a slightly more depolarized resting membrane potential than hippocampal principle cells (about 5e10 mV less negative) (Andersen et al., 2007). Thus, less additional depolarization is needed in order to

Please cite this article in press as: Wiescholleck, V., Manahan-Vaughan, D., Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.01.001

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Table 1 Acute consequences of a single MK801-treatment relevant to schizophrenia. Overview of acute consequences of a single MK801-treatment. We refer to effects as “acute” or “short-term” if the assessment took place hours to maximally 4 days after treatment with MK801. [ e increased, Y e decreased, 4 e unchanged as compared to control conditions. Testing procedure Positive symptoms-related behaviour Locomotion Open field

Stereotypy

Sniffing rating scale

Negative symptoms-like behaviour Social withdrawal Social interaction task

Outcome

References

[, antagonizable by typical and atypical neuroleptics

(Hoffman, 1992; Benvenga and Spaulding, 1988; Heale and Harley, 1990; Dai et al., 1995; Corbett et al., 1995) (Hoffman, 1992; Tiedtke et al., 1990; Manahan-Vaughan et al., 2008a,b)

[, antagonizable by neuroleptics

Y

(Zou et al., 2008; Rung et al., 2005)

Y

(Manahan-Vaughan et al., 2008a,b)

Y

(Benvenga and Spaulding, 1988; Jones et al., 1990; Verma and Moghaddam, 1996; Fraser et al., 1997; Heale and Harley, 1990; Murray and Ridley, 1997)

Y GLUN2C in the entorhinal and YGLUN2B and parietal cortices Induction in PC and RSC

(Lindén et al., 2001)

HSP70

In situ hybridization on rat brain sections Immunocytochemistry

GAD 67 mRNA PV mRNA

In situ hybridization In situ hybridization

Extracellular dopamine levels Dopamine metabolism

HPLC

4 Y in DG after 4 h; Y in mPFC, HC, EC and amygdala after 24 h [ in PFC

Cognitive dysfunction related behaviour Sensorimotor gating Prepulse inhibition of the acoustic startle response Learning and memory Passive avoidance task, spatial delayed alternation task (PFC dependent), spontaneous alternation task, Morris milk maze, conditional Y-maze task Molecular changes NMDAR mRNA

HPLC

Dopamine receptors expression Synaptic transmission Spontaneous firing Firing rate of dopamine neurons Evoked field potentials Synaptic plasticity in vitro LTP Synaptic plasticity in-vivo LTP Paired-pulse

[ in PFC 30 min after Mk801, [ in striatum 120 min after MK801 [ of striatal D1 receptors at 24 h but not 2 h after MK801, [ of D2 receptors in VTA and s.n. [ in mPFC via a hippocampo-prefrontal pathway [ in substantia nigra and VTA

(Hashimoto et al., 1997; Hashimoto et al., 1996) (Romón et al., 2011) (Romón et al., 2011) (Wedzony et al., 1993) (Dai et al., 1995) (Wedzony et al., 1993, 1996)

Single unit recordings in freely moving rats Single cell recordings in anaesthetized rat Stimulus-induced field potentials in brain slice

(Jodo et al., 2005)

Y Stimulus-induced FPs in layer III, but not in layers II and V of the mEC

(Gloveli et al., 1997)

Hippocampal SC-CA1 synapse

Y

(Coan et al., 1987)

Hippocampal PP-Dg synapse, anaesthetized rat Hippocampal PP-Dg synapse, anaesthetized rat

Y

(Abraham and Mason, 1988)

[ 30 s interval

(Lasley and Gilbert, 1996)

Hippocampal slices of rats pretreated with MK801 Oscillations in area CA1 and Dg in freely moving rats

[ kainate-induced gamma frequency field oscillations power in area CA1 [ gamma power

(Kehrer et al., 2007)

2-DG uptake

[ in HC (no effect after amphetamine), limbic cortical regions, thalamus and nucleus accumbens (identical to ketamine), Y in auditory system

(Murase et al., 1993)

Neuronal oscillations

Metabolism Glucose utilization

(Kittelberger et al., 2012)

(Duncan et al., 1999)

PC e posterior cingulate, RSC e retrosplenial cortices, mPFC e medial prefrontal cortex, HC e hippocampus, EC e entorhinal cortex, VTA e ventral tegmental area, HPLC e High-performance liquid chromatography, FP e field potential, PP e perforant pathway, Dg e dentate gyrus, CA1 e area cornu ammonis 1, SC e Shaffer collaterals, 2-DG e 2Deoxy-D-glucose).

activate the interneuronal NMDARs, which again suggests an increased number of NMDARs accessible to MK801 that binds preferentially to open channels. Interestingly, interneurons but not principle cells often express GluN2C subunit-containing NMDARs in adult hippocampus (Monyer et al., 1994). GluN2C subunitcontaining NMDARs have a lower sensitivity to Mg2þ-blockade than GluN2A- and GluN2B-containing receptors (Monyer et al.,

1994). A lower sensitivity to Mg2þ blockade would mean that lower membrane depolarization levels than usually, would be sufficient enough in order to activate the receptor. Thus, GluN2Ccontaining NMDARs in interneurons would already respond to excitation that would usually be too low to remove the Mg2þ block. Consequently, MK801 would be again able to access a higher portion of interneuronal NMDARs as compared to NMDARs of principle

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Table 2 Long-lasting consequences of MK801-treatment relevant to schizophrenia. Overview of long-lasting consequences of MK801-treatment. [ e increased, Y e decreased, 4 e unchanged as compared to control conditions. Treatment mode

Testing procedure

Outcome & duration

Reference

Open field

4 (1 week after treatment)

Activity test New cage activity test

4 (9 d after treatment) [ in adult females but not males (P56)

(Wiescholleck and Manahan-Vaughan, 2012a) (Wozniak et al., 1996) (Harris et al., 2003)

Social interaction task % Time spent in center of open field

4 no effect (7 and 10 d after treatment) 4 1 week after treatment

(Sams-Dodd, 2004) (Wiescholleck and Manahan-Vaughan, 2012a)

Prepulse inhibition Sensorimotor battery Prepulse inhibition

4 7 and 28 d after treatment 4 10 d after treatment Y in adult females but not males (P56)

(Manahan-Vaughan et al., 2008a) (Wozniak et al., 1996) (Harris et al., 2003)

Y reference memory 28 d after treatment Y 1,2,3,4 weeks after treatment Y for 5 months

(Manahan-Vaughan et al., 2008a) (Wiescholleck and Manahan-Vaughan, 2012a) (Wozniak et al., 1996)

Chronic

Radial arm maze Object recognition task (4 h ITI) Modified hole board food search task Morris water maze

Y for 14 d

(Li et al., 2011)

Neonatal (twice on P7) Neonatal (twice on P7)

In situ hybridisation and immunoautoradiography In situ hybridisation and immunoautoradiography

Altered NR1 mRNA in thalamus and HC in adult rats (P60) YmRNA in thalamus of adult rats (P60)

(Harris et al., 2003) (Harris et al., 2003)

Synaptic plasticity in vitro LTP

Single

dCI-CA1 synapse

Yfor 7d

(Wöhrl et al., 2007)

Synaptic plasticity in-vivo LTP

Single

PP-Dg synapse in-vivo

Y 1,2,3,4 weeks after treatment

LTD Basal synaptic transmission

Single Single

PP-Dg synapse in-vivo PP-Dg synapse in-vivo

4 7 and 28d after treatment 4 1 week after treatment

(Wiescholleck and Manahan-Vaughan, 2012a,b; Manahan-Vaughan et al., 2008a) (Manahan-Vaughan et al., 2008b) (Wiescholleck and Manahan-Vaughan, 2012a)

Chronic ketamine

Area CA1 and Dg in-vivo

Y gamma and theta power 2e4 weeks after treatment

(Kittelberger et al., 2012)

Chronic PCP

FDG

[ FDG-uptake 10 d after treatment

(Ellison and Keys, 1996)

Positive symptoms-related behaviour Locomotion Single Single Neonatal (twice on P7) Negative symptoms-like behaviour Social interaction Single Anxiety-related behaviour Single Cognitive dysfunction related behaviour Sensorimotor gating Single Single Neonatal (twice on P7) Learning and memory Single Single Single

Molecular changes NMDAR expression Synaptophysin

Neuronal oscillations

Metabolism Glucose uptake

d e day, P e postnatal day, ITI e intertrial interval, dCl e direct cortical input, CA1 e area cornu ammonis 1, PP e perforant pathway, Dg e dentate gyrus, FDG e Fluordesoxyglucose, PCP e Phencyclidine.

cells. In support of the last point, evidence exists that MK801 binds preferentially to GluN2C-containing NMDARs, as the expression of NMDAR-GluN2C but not -2A, -2B or -2D subunits is significantly decreased in the entorhinal cortex after MK801 administration (Lindén et al., 1997). Taken together, these mechanisms might account for the potential cell type-specific difference in effect of NMDAR antagonists on NMDARs of interneurons and principle cells. 2.8. Possible molecular mechanisms responsible for persistent effects of MK801 on hippocampus-dependent cognition and memory How does an acute irreversible block of NMDARs by MK801 mediate long-lasting effects on hippocampal memory and synaptic plasticity lasting for weeks or even months? And may these changes reflect how a first-episode psychosis changes the human brain on molecular level? As suggested by Olney and others, one mechanism might comprise MK801-induced neurotoxicity (Olney et al., 1989; Farber

et al., 1995). The paradoxical discovery that MK801 (originally designed in order to prevent glutamate excitotoxicity in neurons after e.g. cerebral ischemia) induces specific reversible and sometimes irreversible cell damage in certain brain areas, led to cessation of all ongoing clinical trials with MK801. Olney and colleagues had discovered that in addition to their neuroprotective properties, PCP, ketamine and MK801 at high doses produce intracytoplasmic vacuolization in layer III neurons of the retrosplenial cortex and posterior cingulate (Olney et al., 1991). It has been hypothesized that the vacuoles in principle cells in retrosplenial cortex and posterior cingulate are caused by excessive disinhibition due to antagonism of NMDAR of extra-retrosplenial cortex GABAergic interneurons that project onto cholinergic, noradrenergic and glutamatergic neurons that in turn all converge on retrosplenial cortex neurons (Olney and Farber, 1995). Electron microscopy revealed that specifically mitochondria are involved in the vacuolization process. Hence, the intracytoplasmic vacuoles are due to the dilatation of mitochondria (Fix et al., 1993). Mitochondrial dysfunction might reflect oxidative stress, a mechanism that has been recently strongly implicated in

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schizophrenia pathology (Bitanihirwe and Woo, 2011). Moreover, mitochondrial functioning was shown to be crucial for the expression of synaptic plasticity (Lee et al., 2012). A portion of those vacuolized neurons has been reported to progress into irreversible necrosis in retrosplenial cortex (RS) and posterior cingulate (PC) in a dose-dependent manner (Farber et al., 2002). Apart from the RS/PC, vulnerability to MK801-induced cell damage of other cortical regions has also been reported (Horváth et al., 1997). The literature seems, however, inconsistent regarding vacuolization outside the RS/PC, as others failed to detect any histological changes in regions distinct from RS/PC after MK801treatment (Wöhrl et al., 2007; Shiotani et al., 2011). In the animal model of acute psychosis using a single quite high dose of MK801 (5 mg/kg), Wöhrl et al. (2007) failed to find any signs of vacuolization or neurotoxicity in the entorhinal cortex or CA1 region 24 h after MK801-treatment even in female rats, that are reportedly more sensitive to the effects of MK801 (Auer, 1996). However, Horváth et al. (1997), reported transient neuronal damage in the dentate gyrus after a single treatment with the same dose of MK801 (5 mg/kg) in male rats. The dentate gyrus was the site of chronic LTP impairment resulting from MK801-treatment reported in the abovementioned studies (Manahan-Vaughan et al., 2008a,b; Wiescholleck and Manahan-Vaughan, 2012a,b). Thus, one could speculate that this transient neuronal damage changes the future cell physiology in terms of persistent functional alterations, including the deficit in the ability to induce synaptic plasticity. The neurons seem to “remember” this apparently quite incisive stroke by permanently altered memory- and synaptic plasticity-related functioning. Such long-lasting changes must involve altered gene transcription, which will probably be mediated by epigenetic mechanisms. Indeed, single and chronic treatment with MK801 has been shown to acutely alter the expression of several genes and proteins (Paulson et al., 2003). Several of them relate to synaptic functioning and have been previously connected to schizophrenia pathology (Paulson et al., 2003). However, to our knowledge, no one has yet investigated how MK801-treatment alters gene and protein expression in the long-term and if epigenetic mechanisms, such as e.g. altered DNA-methyltransferase activity or histone modifications, are involved. If speculatively extrapolating this chain of thoughts to the human situation, one might assume that during acute first-episode psychosis, certain neurons may undergo transient vacuolisationlike cellular changes, similar to those induced by MK801. Interestingly, vacuolization has indeed been reported in the temporal lobe of young schizophrenic adults by means of electron microscopy (Mesa-Castillo, 2001). Moreover, impaired mitochondrial network (Rosenfeld et al., 2011), as well as a decrease in mitochondria in certain brain areas (Somerville et al., 2012) has been detected in human post-mortem tissue of schizophrenic patients. We know that if first-episode psychosis is not treated effectively within a certain time window, it may progress into chronic schizophrenic illness (Alvarez-Jimenez et al., 2011). First-episode psychosis seems therefore to make the system more vulnerable towards further pathology. This vulnerability might be caused by the vacuolization of neurons in limbic structures and specifically in RS/PC during the first-episode psychosis, which in turn influences brain functioning on the network level either. As a result, a permanent deficit in synaptic plasticity and memory might occur, which would reflect the higher susceptibility to further psychotic events (Fig. 3). 2.9. Relevance for psychosis research Once the brain has experienced a psychotic event, the vulnerability towards further pathology is substantially increased. It is however, impossible to clearly separate pre-psychotic stages of the

Fig. 3. A possible chain of events underlying progression from a first psychotic episode to chronic schizophrenic illness. Acute psychosis/MK801-induced psychosis-like episode may trigger a chain of molecular events, such as transient formation of intracytoplasmic vacuoles in certain brain areas, resulting in a mitochondrial dysfunction, chronic disrupted synaptic plasticity and cognitive dysfunction. This state persists comprising an increased vulnerability of the brain towards further psychotic events triggered by acute stress.

disease from the “pure” consequences of the psychotic breakdown in humans. The question as to whether the psychotic event itself actively contributes to further pathology can, however, be studied in animals. Indeed, a single MK-801-induced psychotic episode persistently changes the way the brain processes information (Manahan-Vaughan et al., 2008a,b; Wiescholleck and ManahanVaughan, 2012a,b). Although impossible as yet to assess in human brains, these results indicate that these persistent cognitive deficits might be mediated via an impairment in hippocampal synaptic plasticity on the cellular level. Moreover, this might comprise the mechanism which underlies the increased vulnerability of the system after an acute schizophreniform psychosis towards developing further psychotic episodes (Fig. 3). Within the context of the clinical staging model, which assumes that the stages of risk and prodrome precede the psychotic break, the abovementioned findings offer important additional insights. As a single psychotic event actively induces dramatic long-term cognitive and physiological changes, it is possible that the two first stages, risk and prodrome, are necessary to pass the threshold that triggers first-episode psychosis. However, after this happens, it is probably the psychotic event itself that mainly drives further pathology in terms of increased vulnerability for further stressful events. In order to further evaluate this hypothesis, one would need to investigate if animals, that display a persistent impairment in synaptic plasticity after a first psychotic episode, are more susceptible than controls to further stressful/psychosis-like events and their consequences.

Please cite this article in press as: Wiescholleck, V., Manahan-Vaughan, D., Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.01.001

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2.10. Synaptic plasticity e potentially a better indicator for drug efficacy trials? The long-term effects of MK801 on behavioural and synaptic levels represent an interesting and valuable model, which not only provides insights into pathophysiology induced by first-episode psychosis, but also constitutes an important tool in search for effective treatment. The fact that synaptic plasticity impairments in freely moving rats last for a period of at least 4 weeks suggests that this parameter might be the most suitable for preclinical screening tests (Manahan-Vaughan et al., 2008a,b; Wiescholleck and Manahan-Vaughan, 2012b). Almost all of the latest attempts to transfer preclinical findings into human settings have failed. This failure has led to the closure by many pharmaceutical companies of their psychiatry research and development units, due to the high financial risks of developing anti-schizophrenic agents. Usually, preclinical drug efficacy trials are all performed exclusively on the behavioural level in animal models. The assessment as to whether a compound is potentially able to reverse MK801-induced longterm deficits in synaptic plasticity in freely moving animals would possibly add a higher level of efficiency and accuracy to the current preclinical screening procedures. The long-term deficit in the ability to express synaptic plasticity in the MK801 animal model of acute psychosis has already proven to be reliable in terms of testing potential new therapeutic compounds. GlyT-inhibitors, for instance, prevent MK801-induced longterm impairments in the ability to express LTP (Manahan-Vaughan et al., 2008b). In the meantime GlyT-inhibitors are being successfully tested in clinical trials with a significant ameliorative effect on otherwise untreatable negative symptoms (Lane et al., 2010). Recently, the PDE4-inhibitor rolipram was shown to ameliorate MK801-induced long-term deficits in LTP and in object recognition memory (Wiescholleck and Manahan-Vaughan, 2012a). PDE4inhibition thus prevents MK801-induced functional and structural pathology. Due to its quite severe side effects, rolipram will probably not make it directly to clinical trials. However, the mechanism of action, namely inhibition of PDE4 activity, is a promising target for further investigation in schizophrenia spectrum disorders. All in all, changes in certain molecules that act up- or downstream to the NMDAR seem to be able to bypass MK801-induced NMDAR-hypofunction and to save the system from pathological long-term consequences. We hypothesize that specifically the longterm deficits that emerge in this animal model of acute psychosis are more sensitive and persistent, and therefore more suitable as indicators for potentially effective treatment using therapeutic test compounds. Taken together, the abovementioned data support that chronic and potent changes in glutamate receptor-dependent synaptic plasticity in the hippocampus may comprise a key change in brain function that contributes to the pathophysiology of schizophrenia and psychosis. Conflict of interest statement The authors declare that they do not have any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work. References Abraham, W.C., Mason, S.E., 1988. Effects of the NMDA receptor/channel antagonists CPP and MK801 on hippocampal field potentials and long-term potentiation in anesthetized rats. Brain Res. 462, 40e46.

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Please cite this article in press as: Wiescholleck, V., Manahan-Vaughan, D., Long-lasting changes in hippocampal synaptic plasticity and cognition in an animal model of NMDA receptor dysfunction in psychosis, Neuropharmacology (2013), http://dx.doi.org/10.1016/ j.neuropharm.2013.01.001