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Dissertation
PSD-95 deficiency disrupts PFC function and connectivity leading to sociability and cognitive deficits
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2019
DOI:
https://doi.org/10.17918/yfzx-p207
Abstract
Postsynaptic density protein-95 (PSD-95) is a major regulator in the maturation of excitatory synapses by interacting and trafficking N-methyl-D-aspartic acid receptors (NMDARs) and [alpha]-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPARs) to the postsynaptic membrane of the dendritic spine. The medial prefrontal cortex (mPFC)-a brain region responsible for cognition and sociability-contains major reciprocal connections with the mediodorsal thalamus (MD), and this connectivity is severely disrupted in psychiatric disorders such as schizophrenia and autism. Coincidently, PSD-95 disruption has been implicated for both disorders, but how PSD-95 deficiency affects the mPFC during development and MD-mPFC connectivity remains unknown. Therefore, using PSD-95 deficient mouse models (PSD-95+/- & PSD-95-/-), we examined how PSD-95 deficiency affects NMDAR and AMPAR expression and function in the medial prefrontal cortex (mPFC) at postnatal days 21, 35, and 70 i.e., juvenile, adolescent, and adult periods, respectively. We found significant increases in total protein levels of NMDAR subunits GluN1, and GluN2B, accompanied with a significant decrease in AMPAR subunit GluA1 during adolescence. Whole-cell patch clamp recordings of NMDA- and AMPA-mediated currents revealed significant increases in NMDAR/AMPAR-mediated current amplitude during adolescence and adulthood. Behaviorally, we show PSD-95-/- mice exhibit a lack of social exploration and novelty, accompanied with learning and working memory deficits. Additionally, using optogenetics, we characterized cortico-cortical verses thalamo-cortical connections within the mPFC. Our results revealed a significant increase in NMDAR/AMPAR-mediated current amplitude ratio in cortico-cortical connections. In contrast, there is a significant reduction in NMDAR/AMPAR-mediated transmission in MD-mPFC connection in PSD-95+/- and PSD-95-/- mice. These data suggests input specific alterations within the mPFC in response to PSD-95 deficiency. These data indicate that PSD-95 deficiency disrupts mPFC synaptic function, connectivity and mPFC-associated behavior. This study describes the importance of PSD-95 during neurodevelopment in the mPFC and its potential roles in social and cognitive dysregulations.
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Details
- Title
- PSD-95 deficiency disrupts PFC function and connectivity leading to sociability and cognitive deficits
- Creators
- Austin Coley - DU
- Contributors
- Wen-Jun Gao (Advisor) - Drexel University (1970-)Rodrigo A. España (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 155 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 9951; 991014632230204721