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Dissertation
Targeting Prefrontal Parvalbumin Cells to Rescue Cognitive Deficits in a Rodent Model for Schizophrenia
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2020
DOI:
https://doi.org/10.17918/00001245
Abstract
The cognitive symptoms of schizophrenia (SZ) present a significant clinical burden. They are resistant to treatment and are the primary predictor of functional outcomes for patients. Although the neural mechanisms underlying these deficits remain unclear, pathological inhibitory GABAergic signaling likely plays an essential role. Perturbations with parvalbumin (PV)-expressing fast-spiking (FS) interneurons in the prefrontal cortex (PFC) are consistently found in post-mortem studies of patients with SZ, as well as in animal models. Our studies have shown a significant decrease in synaptic inhibition and PV immunostaining in the PFC, along with working memory and cognitive flexibility deficits in the NMDA receptor antagonist MK801 model. The hypothesized association between PV cell abnormalities and impaired cognition in SZ suggests that this cell type's functioning may represent a critical point of convergence in the etiology of SZ, especially for cognitive symptoms. We, therefore, directly targeted PV cell activity in the PFC to rescue such cognitive deficits. We hypothesize that the reduced PV cell activity levels disrupt GABA transmission, which in turn results in disinhibition of excitatory pyramidal cells. This disinhibition leads to an elevated prefrontal excitation/inhibition (E/I) balance, and this could be the key causal factor for cognitive impairments. Indeed, we found that targeted pharmacogenetic upregulation of prefrontal PV interneuron activity using a novel excitatory DREADD can restore E/I balance and improve cognition in the MK801 model. Our study provides novel insights into the causal role of PV cells in cognitive function and has clinical implications for understanding the pathophysiology and treatment of SZ.
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Details
- Title
- Targeting Prefrontal Parvalbumin Cells to Rescue Cognitive Deficits in a Rodent Model for Schizophrenia
- Creators
- Linda Ann Chamberlin
- Contributors
- Wen-Jun Gao (Advisor)Kimberly J. Dougherty (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- viii, 219 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991014695234204721