Inhibition as a mediator of the relation between autism spectrum disorder and victimization

Abstracts / Int. J. Devl Neuroscience 47 (2015) 1–131

dysfunction has not been completely understood. Examination of 6 control human cases between 23 and 26 GW showed that the ventricular zone (VZ) and subventricular zone (SVZ) of the cerebral cortex are composed of layered neural progenitors, suggesting still on-going neurogenesis during this period. In acute case of EPI brains with PWMI, we identified impaired periventricular neural progenitors and long-term survivors showed increased number of ectopic neurons in the white matter. These findings led us to hypothesize that brain injury in EPIs may affect later neurogenesis and neuronal migration, which can cause cognitive impairment. To confirm these human findings, we generated a new mouse model. We induced ischemia in mouse embryos with maternal uterine artery occlusion at E15.5 labelled by in utero electroporation of green fluorescent protein (GFP) to understand pathological mechanisms in detail. We observed decreased number of neuronal progenitors and impaired neuronal migration, resulting in altered neuronal alignment and abnormal axonal targeting. Behaviour testing showed cognitive deficits in mice survived to adolescence. We propose that abnormal brain network on altered neuronal alignment should be considered in the pathogenesis of cognitive dysfunction in EPIs. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.164 ISDN2014 0201 Reactivation of developmental nuclear FGFR1 signaling and neurogenesis in adult brain by ␣7 nicotinic receptor agonist S. Narla ∗ , B. Birkaya, Y.-W. Lee, E.K. Stachowiak, M.K. Stachowiak Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, WNYSTEM, Buffalo, NY, USA Reactivation of endogenous neurogenesis in the adult brain or spinal cord holds the key for treatment of CNS injuries as well as neurodegenerative disorders, which are major healthcare issues for the world’s aging population. We have previously shown that activation of developmental Integrative Nuclear FGFR1 Signaling (INFS), via gene transfection, reactivates neurogenesis in the adult brain by promoting neuronal differentiation of brain Neural Stem/Progenitor Cells (NS/PC). In the present study, we report that targeting the ␣7 nicotinic acetylcholine receptors (␣7nAChR) with a specific TC-7020 agonist leads to a robust accumulation of endogenous FGFR1 in the cell nucleus, markedly diminished proliferation of NS/PC in subventricular zone (SVZ) and generation of new neurons in different regions of the adult mouse brain by promoting neuronal differentiation, including: (1) ␤III Tubulin-expressing cortical neurons, (2) calretinin expressing hippocampal neurons and (3) cells in substantia nigra expressing predopaminergic Nurr1+ phenotype. Furthermore, we show that in vitro stimulation of neural stem/progenitor cells with ␣7nAChR directly activates INFS and neuronal-like differentiation. TC-7020 stimulation of the ␤III Tubulin gene is accompanied by increased binding of FGFR1, CBP and RNA Polymerase II to a Nur77 targeted promoter region. TC-7020 augments Nur77 dependent activation of Nerve Growth Factor inducible-B protein Responsive Element (NBRE)-luciferase indicating that ␣7nAChR upregulation of ␤III-Tubulin involves neurogenic FGFR1-Nur signaling. The reactivation of INFS and neurogenesis in adult brain by the ␣7nAChR agonist may offer new strategy to treat brain injuries, neurodegenerative and neurodevelopmental diseases. This work was supported by NYSTEM contracts C026415 and C026714. TC7020 was provided as a gift by Targacept Inc. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.165

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ISDN2014 0202 Role of the neurotrophin receptor p75NTR in GABAergic synapse maturation in neocortex Elie Baho ∗ , Bidisha Chattopadhyaya, Marisol Lavertu Jolin, Graziella Di Cristo Department of Neurosciences and Pediatrics, Université de Montréal and CHU Ste-Justine Research Center, Canada Basket cells innervate hundreds of postsynaptic targets with synapses clustered around the soma and proximal dendrites. They are important for gamma oscillation generation and for the regulation of developmental cortical plasticity. Although the function of basket cells within cortical networks is being explored, the mechanisms that control the development of their extensive arborisation and synaptic contacts have not been entirely resolved. Tropomyosin-related kinase B (TrkB) receptor signalling activated by Brain-Derived Neurotrophic Factor (BDNF) binding strongly modulates the maturation of GABAergic synapses, including synapses formed by basket cells. Whether the low-affinity neurotrophin-receptor p75NTR also play a role in the development of basket cell synaptic territory is unknown. Here, we show that single-cell deletion of p75NTR in basket cells in cortical organotypic cultures from p75NTRlox mice induces the formation of exuberant perisomatic innervations by the mutant basket cells, in a cell-autonomous fashion. BDNF is synthesized as a precursor, proBDNF, which is cleaved by enzymes, including tPA-activated plasmin, to produce mature (m)BDNF. mBDNF and proBDNF bind with high-affinity TrkB and p75NTR, respectively. Our results show that treating organotypic cultures with cleavage-resistant proBDNF (mut-proBDNF) strongly reduces the synaptic territory of basket cells. Treating cultures with the tPAinactivating peptide PPACK or with tPA impairs and promotes the maturation of basket cell synaptic innervations, respectively. We further show that the exuberant innervations formed by p75NTR−/− basket cells are not affected by mut-proBDNF treatment. All together, these results suggest that proBDNF-mediated p75NTR activation negatively regulates the synaptic territory of basket cells. We next examined if mut-proBDNF affects perisomatic innervation formed by basket cells in vivo, in the adult mouse. We found that perisomatic GABAergic boutons are significantly decreased in the cortex infused with mut-proBDNF as compared to non-infused or saline-treated hemispheres. We are currently investigating whether alterations of p75NTR signaling affects cortical plasticity in the adult. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.166 ISDN2014 0203 Inhibition as a mediator of the relation between autism spectrum disorder and victimization C.C. Hudson ∗ , E.A. Kelley, P.H. Kloosterman Queen’s University, Canada Introduction: Autism spectrum disorder (ASD) is a neurological developmental disorder that involves poor social communication and social interaction (American Psychiatric Association, 2013). Recent literature suggests that individuals with ASD are experience higher rates of victimization than their typically developing (TD) peers (Rose et al., 2009). Researchers have not investigated the factors that may be associated with victimization in children and adolescents with ASD.

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Abstracts / Int. J. Devl Neuroscience 47 (2015) 1–131

Individuals with ASD often demonstrate difficulties with behavioural inhibition (Adams and Jarrold, 2012). This can cause individuals with ASD to exhibit socially inappropriate behaviour that may make them an “easy target” for victimization. The current study investigated the hypothesis that inhibition mediates the relation between diagnosis (ASD, TD) and victimization. Methods: Fifty-one male participants were recruited (Mage = 14.39, range = 11.57–18.59). Thirty-two participants did not have an ASD diagnosis and 19 participants met criteria for ASD. Victimization experiences were evaluated using the WHO bullying and victimization questionnaire. Parent’s indicated the victimization their children experienced in the past 3 months. Inhibition was measured using the Behavioural Rating Inventory for Executive Functioning (Gioia et al., 2000). Results: A mediation analysis was run using Hayes’s (2013) PROCESS macro. Consistent with the hypothesis, inhibition fully mediated the relation between diagnosis (ASD, TD) and victimization. A bias-corrected bootstrap confidence interval for the indirect effect (b = .8452) based on 10,000 bootstrap samples was above zero (.3035 to 1.54) indicating the indirect effect was significant. Consistent with previous research, diagnosis was significantly related to victimization, b = 1.2155, t(49) = 3.67, p < .001; however, diagnosis was no longer significantly related to victimization controlling for inhibition b = .37, t(48) = .95, p = .35. Discussions: Results suggest that diagnostic differences in victimization are fully accounted for by differences in inhibition. Implications for bullying intervention and prevention programs are discussed. http://dx.doi.org/10.1016/j.ijdevneu.2015.04.167 ISDN2014 0204 Performance- and questionnaire-based tools for the evaluation of executive function in children and adolescents with fetal alcohol spectrum disorder Kaitlyn McLachlan 1,2,∗ , Jacqueline Pei 3 , Katrina Kully-Martens 3 , Angelina Paolozza 4 , Tim F. Oberlander 2 , Christine Loock 5 , Gail Andrew 6 , James Reynolds 4 , Carmen Rasmussen 1 1

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada 2 Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada 3 Department of Educational Psychology, University of Alberta, Edmonton, AB, Canada 4 Centre for Neuroscience Studies, Queens University, Kingston, ON, Canada 5 Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada 6 Glenrose Rehabilitation Hospital, Edmonton, AB, Canada Background: Both performance- and questionnaire-based measures of executive functioning (EF) are commonly in neuropsychological assessments of fetal alcohol spectrum disorder (FASD), a key neuropsychological deficits often observed in this population. Although both types of measures purportedly measure EF, they often provide discrepant results in other clinical populations (Toplak et al., 2013). In addition, the majority of published measures assess “cool” or cognition-based EF, rather than “hot” or emotionrelated EF. The present study assessed the concordance of data derived from both cool (NEPSY-II) and hot (Iowa Gambling Task, IGT) performance-based EF measures, and a questionnaire-based

EF tool (Behavior Rating Inventory of Executive Function, BRIEF) among youth with prenatal alcohol exposure (PAE). Methods: 67 children and adolescents with PAE, ages 5 to 16 (M = 11.1, SD = 2.6, 52% female) completed neuropsychological measures during the NeuroDevNet FASD study. Results: A substantial proportion of the sample had impairments in EF, with 49.2% earning scores two or more standard deviations worse than normative means on one or more scales from the NEPSY-II and BRIEF. However, agreement between the two measures was poor, with only 30.2% earning comparable scores. There were no significant correlations between the BRIEF and NEPSY-II scales. Alternatively, IGT scores were highly correlated with several NEPSY-II (r = .41 to .50, p = .02 to .04), and BRIEF scales (r = −.45, −.48, p = .02 to .04). Conclusions: Clinicians evaluating EF among youth referred for FASD assessments should be aware of these discrepancies and consider the need for careful integration of findings from multiple assessment methods. It is possible that performance and questionnaire-based EF tools assess different aspects of the EF construct, and/or, that questionnaires such as the BRIEF capture real world behavioural problems that may or may not map onto underlying EF deficits (Toplak et al., 2013). http://dx.doi.org/10.1016/j.ijdevneu.2015.04.168 ISDN2014 0205 Intrauterine growth restriction-induced cerebral palsy: Evaluating histological and behavioural differences in a translational rodent model C.A. Ruff a,∗,1 , S.D. Faulkner a,1 , E. Armstrong b , A. Basilious a , S. Fan a , S. Thiyagalingam a , J.Y. Yager b , M.G. Fehlings a a

Division of Genetics and Development, Department of Surgery, Toronto Western Research Institute (TWRI), University Health Network (UHN), Canada b Department of Paediatrics, University of Alberta, Edmonton, Canada With prevalence of ∼2.3/1000 births, Cerebral Palsy (CP) is the most common paediatric neurodevelopmental physical disability. Spastic diplegia, its most common phenotype, affects 35% of these children, causing severe motor and developmental disturbances. Pre-oligodendrocytes are particularly susceptible to ischemic insult, and periventricular leukomalacia (PVL) results when periventricular regions, which spatially overlap descending corticospinal tracts, are damaged by chronic placental insufficiency (PI). Translationally relevant models of PVL, via intrauterine growth restriction (IUGR) and PI are necessary to elucidate human mechanisms of disease and to evaluate cellular/biological CP interventions. Five anaesthetized, pregnant LE rats underwent bilateral uterine artery ligation at E20 (3 SHAM, 2 IUGR) to induce placental insufficiency, IUGR and subsequent diplegia in offspring (n = 11 SHAM, n = 15 IUGR). Between P21-P180, pups underwent weekly behavioural gait analysis. At P180, animals were culled and examined histologically. Body weight was lower in IUGR vs. SHAM rats at P0/P21 (P < 0.001) and normalized thereafter. Histologically, animals with IUGR exhibited thinned corpus callosum (CC) with reduced area (P < 0.025), which did not nor-

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Authors contributed equally to this Abstract.