NMDA receptor dysfunction in the developing prefrontal cortex in two animal models for schizophrenia: expression profile, epigenetic mechanisms, and physiology

Schizophrenia is a highly debilitating illness often diagnosed in late adolescence and early adulthood following the emergence of psychotic symptoms. In addition to psychosis, negative symptoms and cognitive deficits are characteristic of the disorder, and are often evident prior to diagnosis. While positive symptoms are often attenuated with antipsychotic treatment, cognitive dysfunctions are unresponsive to therapeutic agents and persist throughout the course of the illness. As the best determinant of functional outcome, targeting the pathophysiology of cognitive deficits has become a priority for government agencies, academic research institutions, and the pharmaceutical industry. Among the prominent hypotheses attributed to schizophrenia, cortical hypofunction of the glutamate neurotransmitter system is an appealing possibility due to the importance of N-methyl-D-aspartate receptors (NMDARs), a type of ionotropic receptor, in brain development and cognition. Interestingly, blocking NMDARs during juvenile development is sufficient to elicit schizophrenia-like phenotypes in adult animals. Further, schizophrenic subjects display significant prefrontal hypofunction during performance of cognitive tasks. Compelled by the importance of the NMDAR system in the development and maturation of the prefrontal cortex, this work explores the expression profile and functional properties of the NMDAR system during juvenile and adolescent development in two animal models for schizophrenia: the neurodevelopmental MAM model and the inducible hDISC1 mutant mouse model. We confirm that NMDAR hypofunction is a feature of prefrontal development in these two models, albeit by changes in expression of divergent subunits. Further, we explore a mechanism by which NMDAR expression changes occur in the juvenile prefrontal cortex, implicating aberrant epigenetic regulation of the NR2B subunit. These data support the neurodevelopmental hypofunction hypothesis and highlight the importance of investigating early prefrontal dysfunction to understand the complex pathology observed in the chronic stage of schizophrenia.Ph.D., Neuroscience -- Drexel University, 201

Distinct properties of layer 3 pyramidal neurons from prefrontal and parietal areas of the monkey neocortex

In primates, working memory function depends on activity in a distributed network of cortical areas that display different patterns of delay task-related activity. These differences are correlated with, and might depend on, distinctive properties of the neurons located in each area. For example, layer 3 pyramidal neurons (L3PNs) differ significantly between primary visual and dorsolateral prefrontal (DLPFC) cortices. However, to what extent L3PNs differ between DLPFC and other association cortical areas is less clear. Hence, we compared the properties of L3PNs in monkey DLPFC versus posterior parietal cortex (PPC), a key node in the cortical working memory network. Using patch-clamp recordings and biocytin cell filling in acute brain slices, we assessed the physiology and morphology of L3PNs from monkey DLPFC and PPC. The L3PN transcriptome was studied using laser microdissection combined with DNA microarray or quantitative PCR. We found that in both DLPFC and PPC, L3PNs were divided into regular spiking (RS-L3PNs) and bursting (B-L3PNs) physiological subtypes. Whereas regional differences in single-cell excitability were modest, B-L3PNs were rare in PPC (RS-L3PN:BL3PN, 94:6), but were abundant in DLPFC (50:50), showing greater physiological diversity. Moreover, DLPFC L3PNs display larger and more complex basal dendrites with higher dendritic spine density. Additionally, we found differential expression of hundreds of genes, suggesting a transcriptional basis for the differences in L3PN phenotype between DLPFC and PPC. These data show that the previously observed differences between DLPFC and PPC neuron activity during working memory tasks are associated with diversity in the cellular/ molecular properties of L3PNs.Fil: Gonzalez Burgos, Guillermo. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Miyamae, Takeaki. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Krimer, Yosef. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Gulchina, Yelena. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Pafundo, Diego Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Krimer, Olga. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Bazmi, Holly. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Arion, Dominique. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Enwright, John F.. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Fish, Kenneth N.. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Lewis, David A.. Univeristy of Pittsburgh. School of Medicine; Estados Unido