Functional outcome in individuals with schizophrenia and related disorders is primarily determined by the degree of impairment in certain core cognitive abilities. For example, subjects with schizophrenia exhibit deficits in visual working memory and attention, and altered patterns of cortical activity during tasks that tap these abilities. These patterns of activity depend on the proper temporal firing of neurons distributed across a network that includes primary visual (VI), posterior parietal (PPC) and dorsolateral prefrontal DLPFC) cortices. These findings highlight an unanswered critical question: What are the cortical cellular, circuitry and connectivity bases for the impairments in visual working memory and attention in schizophrenia? To answer this question, the complementary studies in the proposed Center are designed to test the following Central Hypothesis: Intrinsic molecular disturbances in layer 3 pyramidal cells of the neocortex give rise to morphological abnormalities in these neurons. The severity of this cellular pathology is moderated across cortical regions as a function of normal regional differences in the properties of layer 3 pyramidal cells. This cellulr pathology alters cortical circuitry within and between regions, impairs functional connectivity across regions, and results in disturbances in both bottom up and top down processes during visual working memory and attention in individuals with schizophrenia. The five inter-related projects (P) of the proposed Center provide convergent tests of this hypothesis at the molecular, cellular, laminar and local circuitry levels in postmortem human brain (P1&P2), and at the regional and distributed circuitry levels through imaging and neurophysiological studies in never-medicated subjects with a first-episode of psychosis (P5);these studies are both informed and constrained by parallel studies in monkeys (P3&P4). A key innovation of this approach is the integration of studies with multiple levels of resolution, from molecules to behavior, that provide a translational assessment of both bottom up and top down explanations of cortical dysfunction in schizophrenia.

Public Health Relevance

The proposed studies have high clinical relevance as the combination of molecular-cellular-circuit level analyses with in vivo indices of brain function offers a platform for subsequent identification of novel, pathologically-based targets for therapeutic interventions that are accompanied by pathophysiologically informed biomarkers that can be used to predict and monitor the efficacy of such interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH103204-01
Application #
8666277
Study Section
Special Emphasis Panel (ZMH1-ERB-L (01))
Program Officer
Zalcman, Steven J
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$2,149,999
Indirect Cost
$668,436
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Glausier, Jill R; Lewis, David A (2017) GABA and schizophrenia: Where we stand and where we need to go. Schizophr Res 181:2-3
Forsyth, Jennifer K; Lewis, David A (2017) Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features. Trends Cogn Sci 21:760-778
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Arion, Dominique; Huo, Zhiguang; Enwright, John F et al. (2017) Transcriptome Alterations in Prefrontal Pyramidal Cells Distinguish Schizophrenia From Bipolar and Major Depressive Disorders. Biol Psychiatry 82:594-600
Miyamae, Takeaki; Chen, Kehui; Lewis, David A et al. (2017) Distinct Physiological Maturation of Parvalbumin-Positive Neuron Subtypes in Mouse Prefrontal Cortex. J Neurosci 37:4883-4902
Jalbrzikowski, Maria; Murty, Vishnu P; Stan, Patricia L et al. (2017) Differentiating between clinical and behavioral phenotypes in first-episode psychosis during maintenance of visuospatial working memory. Schizophr Res :
Dorph-Petersen, Karl-Anton; Lewis, David A (2017) Postmortem structural studies of the thalamus in schizophrenia. Schizophr Res 180:28-35
Enwright Iii, J F; Huo, Z; Arion, D et al. (2017) Transcriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia. Mol Psychiatry :

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