Dienel, Samuel
(2023)
Somatostatin Neurons in Prefrontal Cortical Microcircuits in Schizophrenia.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Certain cognitive functions, including working memory, are impaired in individuals with schizophrenia. These cognitive impairments are key predictors of functional outcomes in this patient population, but there are no available therapeutic options to ameliorate these impairments. Only postmortem studies of the brain can reveal alterations in the cortical circuitry in schizophrenia that could underlie these cognitive disturbances and inform therapeutic intervention. Proper working memory function requires robust resistance to distracting information, and it appears that working memory deficits in schizophrenia reflect, at least in part, heightened susceptibility to distractors. The capacity for working memory generally, and especially for filtering out distracting information, is heavily dependent on activity in the dorsolateral prefrontal cortex (DLPFC). Convergent lines of evidence suggest that within the DLPFC, dendritic inhibition, provided from GABA neurons expressing the neuropeptide somatostatin (SST), is crucial for mediating distractor resistance in the DLPFC. The DLPFC, relative to other cortical regions, is enriched for SST mRNA, supporting the idea that SST neurons contribute to a distractor-resistant circuit. In schizophrenia, SST mRNA levels are markedly lower in the DLPFC, suggesting that impairment of these neurons in the disorder render these individuals more susceptible to distractors during working memory. Here, this dissertation work elucidates the basis for these differences in mRNA levels. In the first chapter, we find that higher SST in the DLPFC relative to the primary visual cortex reflects a greater proportion of SST neurons in the DLPFC, rather than SST levels per neuron. In contrast, in the second chapter, we find that deficits in SST mRNA in the DLPFC of schizophrenia primarily reflect lower gene expression per neuron without a deficit in neuron density. Finally, in the third chapter, we find that SST neurons exhibit lower levels of key GABA synthesizing enzymes in schizophrenia, indicating that these neurons have an impaired capacity to provide inhibition. The results of this dissertation reveal the nature of SST neuron disturbances in the DLPFC in schizophrenia, inform the putative impact of these alterations in the context of working memory, and offer insight for novel therapeutic interventions aimed at ameliorating the cognitive burden in the disorder.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
7 April 2023 |
| Date Type: |
Publication |
| Defense Date: |
13 July 2022 |
| Approval Date: |
7 April 2023 |
| Submission Date: |
28 July 2022 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
289 |
| 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: |
GABA, cognition, working memory, parvalbumin, calretinin, human, postmortem |
| Date Deposited: |
07 Apr 2023 18:16 |
| Last Modified: |
07 Apr 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43655 |
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Somatostatin Neurons in Prefrontal Cortical Microcircuits in Schizophrenia. (deposited 07 Apr 2023 18:16)
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