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PYRAMIDAL CELLS: ROLE IN PRIMATE PREFRONTAL CORTEX CIRCUITRY DURING POSTNATAL DEVELOPMENT AND SCHIZOPHRENIA

Datta, Dibyadeep (2016) PYRAMIDAL CELLS: ROLE IN PRIMATE PREFRONTAL CORTEX CIRCUITRY DURING POSTNATAL DEVELOPMENT AND SCHIZOPHRENIA. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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 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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Datta, Dibyadeepdid18@pitt.eduDID18
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLewis, David Alewisda@upmc.eduTNPLEWIS
Committee MemberCard, J Patrickcard@pitt.eduCARD
Committee MemberFish, Kenneth Nfishkn@upmc.edu
Committee MemberSibille, Etienneets7@pitt.eduETS7
Committee MemberMeriney, Stevenmeriney@pitt.eduMERINEY
Committee MemberSohal, Vikaasvikaas.sohal@ucsf.edu
Date: 19 January 2016
Date Type: Publication
Defense Date: 24 September 2015
Approval Date: 19 January 2016
Submission Date: 9 November 2015
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 219
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Dendritic spines, Rho GTPases, Development, DLPFC, GABA
Date Deposited: 19 Jan 2016 16:44
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/26327

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