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Distinct roles for different Homer1 isoforms in behaviors and associated prefrontal cortex function.
Kevin D Lominac1, Erik B Oleson, Matthew Pava
1Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Summary
Investigating Homer1 gene variants in mice reveals distinct roles for Homer1a and Homer1c isoforms in the prefrontal cortex (PFC). These findings offer insights into schizophrenia-like behaviors and glutamate regulation.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Homer1 mutant mice display schizophrenia-like behavioral and neurochemical deficits.
- The Homer1 gene produces both immediate early gene (IEG) and constitutively expressed (CC) products.
Purpose of the Study:
- To differentiate the roles of IEG and CC Homer1 isoforms in the prefrontal cortex (PFC) using viral vector delivery.
- To investigate the impact of Homer1a and Homer1c isoforms on schizophrenia-like phenotypes.
Main Methods:
- Local infusion of adeno-associated viral vectors carrying different Homer1 transcriptional variants into the PFC of mutant mice.
- Assessment of behavioral adaptation, sensorimotor and cognitive processing, and cocaine sensitivity.
- Measurement of prefrontal cortex basal and cocaine-induced glutamate levels.
Main Results:
- PFC Homer1a overexpression normalized stress adaptation, while Homer1c overexpression corrected sensorimotor, cognitive, and cocaine sensitivity deficits.
- Homer1a affected cocaine-induced glutamate response but not basal levels.
- Homer1c modulated basal glutamate levels and enhanced cocaine-induced glutamate release.
Conclusions:
- Homer1a and Homer1c isoforms play distinct roles in PFC-mediated behaviors.
- These isoforms are critical for regulating basal glutamate and its release, relevant to schizophrenia and stimulant abuse comorbidity.