Files and links (1)
Published, Version of Record (VoR)Open Access (License Unspecified), Open
Journal article
Pharmacogenetic activation of parvalbumin interneurons in the prefrontal cortex rescues cognitive deficits induced by adolescent MK801 administration
Neuropsychopharmacology (New York, N.Y.)
11 Apr 2023
PMID: 37041206
Abstract
The cognitive symptoms of schizophrenia (SZ) present a significant clinical burden. They are treatment resistant and are the primary predictor of functional outcomes. Although the neural mechanisms underlying these deficits remain unclear, pathological 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 decreased prefrontal synaptic inhibition and PV immunostaining, along with working memory and cognitive flexibility deficits in the MK801 model. To test the hypothesized association between PV cell perturbations and impaired cognition in SZ, we activated prefrontal PV cells by using an excitatory DREADD viral vector with a PV promoter to rescue the cognitive deficits induced by adolescent MK801 administration in female rats. We found that targeted pharmacogenetic upregulation of prefrontal PV interneuron activity can restore E/I balance and improve cognition in the MK801 model. Our findings support the hypothesis that the reduced PV cell activity levels disrupt GABA transmission, resulting in the disinhibition of excitatory pyramidal cells. This disinhibition leads to an elevated prefrontal excitation/inhibition (E/I) balance that could be causal for cognitive impairments. Our study provides novel insights into the causal role of PV cells in cognitive function and has clinical implications for understanding the pathophysiology and management of SZ.
Metrics
Details
- Title
- Pharmacogenetic activation of parvalbumin interneurons in the prefrontal cortex rescues cognitive deficits induced by adolescent MK801 administration
- Creators
- Linda A Chamberlin - Drexel UniversitySha-Sha Yang - Drexel UniversityErin P McEachern - Drexel UniversityJoshua T M Lucas - Drexel UniversityOwen W McLeod Ii - Drexel UniversityClaire A Rolland - Drexel UniversityNancy R Mack - Drexel UniversityBrielle R Ferguson - Drexel UniversityWen-Jun Gao - Drexel University
- Publication Details
- Neuropsychopharmacology (New York, N.Y.)
- Publisher
- Springer Nature
- Number of pages
- 10
- Grant note
- R21MH111609 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH085666 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) 2016 CURE / Pennsylvania Department of Health (PDH)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000967872000002
- Scopus ID
- 2-s2.0-85152401288
- Other Identifier
- 991020418417804721
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences
- Pharmacology & Pharmacy
- Psychiatry