Hoftman, Gil
(2013)
DEVELOPMENT OF CORTICAL GABA CIRCUITRY: IDENTIFYING PERIODS OF VULNERABILITY TO SCHIZOPHRENIA.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The development of cognitive functioning is disrupted in many individuals who will later be diagnosed with schizophrenia, lagging behind healthy comparison subjects by 1-2 standard deviations at clinical onset. Cognitive dysfunction often appears years before clinical onset, is the best predictor of functional outcome, and is increasingly recognized as a central feature of schizophrenia. The domains of cognitive functioning affected in schizophrenia are mediated, at least in part, by prefrontal cortex (PFC) GABA neurons, which show molecular alterations in postmortem studies in schizophrenia. One common environmental risk factor for schizophrenia is chronic cannabis use, which disrupts cognitive function most prominently during adolescence, a time of flux in PFC circuitry that may be a sensitive period for the effects of cannabis use on neural circuit maturation. Parvalbumin (PV)-containing GABA neurons may be particularly vulnerable to risk factors for schizophrenia since they are altered in the disease, important for neural activity associated with cognitive functioning, and have a lengthy period of postnatal maturation. However, the nature of PV neuron subtype-specific developmental changes is not clear. Therefore, this dissertation focuses on understanding the timing of altered expression profiles of GABA-related mRNA levels in schizophrenia, the impact of chronic cannabis exposure during adolescence on GABA circuits of the monkey PFC, and the cell type-specific nature of postnatal maturation of influential GABAergic connections. Indeed, we find that the profile of GABA transmission markers in postmortem PFC tissue in schizophrenia can be explained by disrupted development of their mRNA levels; that chronic exposure to the psychoactive compound in cannabis during adolescence alters the GABAergic mRNA levels in monkey PFC; and that two populations of PV neurons have distinctive modes of maturation in monkey PFC.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
28 September 2013 |
| Date Type: |
Publication |
| Defense Date: |
3 June 2013 |
| Approval Date: |
28 September 2013 |
| Submission Date: |
24 July 2013 |
| Access Restriction: |
4 year -- Restrict access to University of Pittsburgh for a period of 4 years. |
| Number of Pages: |
174 |
| 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: |
Development, Schizophrenia, Sensitive Period, Parvalbumin, Cannabis, Prefrontal Cortex, GABA |
| Date Deposited: |
28 Sep 2013 23:41 |
| Last Modified: |
28 Sep 2017 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/19455 |
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