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Pyramidal Cells: Role in Primate Prefrontal Cortex Circuitry During Postnatal Development and Schizophrenia

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Pyramidal Cells: Role in Primate Prefrontal Cortex Circuitry During Postnatal Development and Schizophrenia PYRAMIDAL CELLS: ROLE IN PRIMATE PREFRONTAL CORTEX CIRCUITRY DURING POSTNATAL DEVELOPMENT AND SCHIZOPHRENIA by Dibyadeep Datta Bachelor of Arts, Neuroscience, Colgate University, 2010 Submitted to the Graduate Faculty of the Kenneth P. Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2015 UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This dissertation was presented by Dibyadeep Datta It was defended on September 24, 2015 and approved by Vikaas Sohal, MD/PhD, Department of Neuroscience, University of California, San Francisco J. Patrick Card, PhD, Department of Neuroscience Kenneth N. Fish, PhD, Department of Psychiatry Stephen D. Meriney, PhD, Department of Neuroscience Etienne L. Sibille, PhD, Centre for Addiction and Mental Health Dissertation Advisor: David A. Lewis, MD, Department of Psychiatry ii Copyright © by Dibyadeep Datta 2015 iii PYRAMIDAL CELLS: ROLE IN PRIMATE PREFRONTAL CORTEX CIRCUITRY DURING POSTNATAL DEVELOPMENT AND SCHIZOPHRENIA Dibyadeep Datta, PhD University of Pittsburgh, 2015 Cognitive deficits constitute a core feature of schizophrenia, are persistent across the course of the illness and are the best predictor of long-term functional outcome. Dysfunction in certain cognitive processes, such as working memory, are common in subjects with schizophrenia and have been attributed to aberrant function of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to reflect, at least in part, alterations in excitatory neurotransmission. Cortical pyramidal neurons, the principal source of cortical glutamate neurotransmission, exhibit highly robust molecular and morphological alterations in schizophrenia. These alterations appear to be most pronounced in DLPFC deep layer 3, the same microcircuit necessary for the generation of neural oscillations in the γ-frequency range that sustain working memory function. Understanding how dysfunction in DLPFC cortical circuits in deep layer 3 might give rise to the pathophysiology of altered γ-frequency oscillations and working memory deficits in schizophrenia require an interrogation of the mechanisms by which these neuropathological alterations may arise, but also the normal developmental trajectories of these vulnerable microcircuits. In this dissertation, we provide evidence for pyramidal cell type- specific molecular disturbances and synapse-specific structural impairments in DLPFC deep layer 3, and cell type-specific and layer-specific nature of postnatal developmental refinements in pyramidal cells in the DLPFC, within the circuitry that subserves γ-frequency oscillations and working memory. Accordingly, we have identified alterations in the expression of numerous molecular regulators of the actin cytoskeleton in a layer-specific and cell type-specific manner in DLPFC deep layer 3 in individuals with schizophrenia that might be a critical “upstream” cause iv in the pathogenesis of the illness. Additionally, using novel triple-label fluorescence immunohistochemistry and spinning-disk confocal microscopy, we characterize specific synaptic connections onto DLPFC deep layer 3 pyramidal cells in schizophrenia. Finally, we demonstrate that the developmental trajectories of primate DLPFC deep layer 3 pyramidal neurons are protracted, and layer-specific and posit that the molecular maturation of GABA synapses on pyramidal cells may account, at least in part, for the maturation of synchronized pyramidal cell firing which is crucial for γ-frequency oscillations. v TABLE OF CONTENTS PREFACE ................................................................................................................... XXI 1.0 GENERAL INTRODUCTION ........................................................................... 1 1.1 OVERVIEW OF SCHIZOPHRENIA .......................................................... 1 1.1.1 Burden of schizophrenia .................................................................... 1 1.1.2 Etiology of Schizophrenia .................................................................. 2 1.1.3 Epidemiology and clinical features of schizophrenia ...................... 4 1.1.4 Cognitive impairments as a critical component of schizophrenia . 6 1.1.5 Treatment and outcome ..................................................................... 7 1.2 DORSOLATERAL PREFRONTAL CORTEX AND PYRAMIDAL CELLS: CRITICAL MEDIATORS OF WORKING MEMORY AND COGNITIVE FUNCTION ................................................................................................................................. 8 1.2.1 Cognitive dysfunction and the dorsolateral prefrontal cortex in schizophrenia ................................................................................................. 8 1.2.2 Deep layer 3 pyramidal cells: “cellular” basis of working memory ..............................................................................................................10 1.2.3 Cortical pyramidal neurons in different laminar locations subserve unique functions .......................................................................................... 11 1.2.4 Spatial tuning of deep layer 3 pyramidal cells is determined by GABA interneurons ...................................................................................... 15 vi 1.2.5 Role of DLPFC GABA interneurons in sculpting pyramidal cell activity for cognitive control ....................................................................... 16 1.2.6 Molecular heterogeneity in GABA receptors .................................. 18 1.3 EVIDENCE FOR ALTERED EXCITATION AND INHIBITION IN SCHIZOPHRENIA ................................................................................................. 21 1.3.1 Aberration in excitatory neurotransmission in schizophrenia ..... 21 1.3.2 Dendritic spines: structure and function ........................................ 23 1.3.3 Actin cytoskeleton: Crucial regulators of Dendritic Spines .......... 25 1.3.4 Impairments in actin cytoskeleton in schizophrenia ..................... 29 1.3.5 Alterations in presynaptic afferents in the DLPFC: Potential source of dendritic spine alterations .......................................................... 31 1.3.6 Alterations in GABA interneurons are most pronounced in DLPFC deep layer 3 in schizophrenia ..................................................................... 33 1.4 DEVELOPMENTAL REFINEMENTS IN DLPFC DEEP LAYER 3 MICROCIRCUITS DURING POSTNATAL MATURATION ................................... 37 1.4.1 Protracted developmental maturation of pyramidal and GABA cells.................................................................................................................37 1.4.2 Pyramidal cell and GABA interneuron circuitry in layer 3 is crucial for generating γ oscillations ....................................................................... 41 1.5 GOALS AND RELEVANCE OF THIS DISSERTATION ........................ 43 2.0 ALTERED EXPRESSION OF CDC42 SIGNALING PATHWAY COMPONENTS IN CORTICAL LAYER 3 PYRAMIDAL CELLS IN SCHIZOPHRENIA .......................................................................................................................................45 vii 2.1 INTRODUCTION .................................................................................... 45 2.2 MATERIALS AND METHODS ............................................................... 50 2.2.1 Human subjects ................................................................................ 50 2.2.2 Laser microdissection procedure.................................................... 52 2.2.3 qPCR analyses .................................................................................. 54 2.2.4 Microarray analyses .......................................................................... 54 2.2.5 Antipsychotic-exposed monkeys .................................................... 55 2.2.6 Data analysis and statistics ............................................................. 55 2.3 RESULTS ............................................................................................... 57 2.3.1 Expression of CDC42-related mRNAs in DLPFC deep layer 3 ...... 57 2.3.2 Effects of psychotropic medications and other confounding variables ........................................................................................................ 61 2.4 DISCUSSION ......................................................................................... 64 2.4.1 Differences in layer-specific vs. cell type-specific pathology in schizophrenia ............................................................................................... 65 2.4.2 Contribution of CDC42-related signaling to dendritic spine abnormalities in DLPFC layer 3 pyramidal cells ........................................ 66 2.4.3 Conclusion ........................................................................................ 68 3.0 IDENTITY OF INPUTS TO DENDRITIC SPINES ON DEEP LAYER 3 PYRAMIDAL CELLS IN THE DORSOLATERAL PREFRONTAL CORTEX IN SCHIZOPHRENIA......................................................................................................... 70 3.1 INTRODUCTION .................................................................................... 70 3.2 MATERIALS AND METHODS ............................................................... 73 viii 3.2.1 Human Subjects ................................................................................ 73 3.2.2 Immunohistochemistry ....................................................................
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