Journal article
F22. UPREGULATING A REDUCED POPULATION OF PREFRONTAL PARVALBUMIN INTERNEURONS TO RESTORE COGNITIVE FUNCTION IN SCHIZOPHRENIA
Schizophrenia bulletin, Vol.45(Supplement_2), pp.S262-S263
09 Apr 2019
PMCID: PMC6455181
Abstract
Abstract
Background
Schizophrenia (SZ) is most recognized by its psychotic symptoms, yet the cognitive deficits are more predictive of functional outcome and less responsive to treatment. The neuropathology underlying cognitive deficits remains elusive, but alterations in GABAergic interneurons are believed to play an essential role. One such alteration observed in human patients and animal models is a reduced number of parvalbumin (PV)-expressing interneurons in the prefrontal cortex (PFC). Such a loss of inhibitory GABAergic cells could disrupt the balance between excitation and inhibition (E/I) in ways that affect cognition.
Methods
In this study, we examine whether increasing the activity of the prefrontal PV cells that remain is sufficient to normalize E/I balance and rescue cognition in an animal model of SZ. To generate this model, we administer an NMDA antagonist (MK801) to adolescent rats, which reduces prefrontal PV cell number and recapitulates many of the behavioral endophenotypes of SZ. To increase the activity of remaining PV cells, we inject a virus into the PFC delivering a PV-promoter driven excitatory DREADD. Subsequent administration of CNO activates the DREADD, increasing the activity of transfected PV cells. We examine the effects of this intervention on E/I balance through whole cell patch clamp electrophysiology, and the effects on different aspects of cognition through the T-maze working memory task and the set shifting cognitive flexibility task.
Results
Our electrophysiological data indicate an elevated prefrontal E/I ratio in MK801-treated female rats, but not in male rats. The altered E/I balance in females is brought back to control levels by CNO activation of DREADD-expressing prefrontal PV cells. To further characterize sex differences, we compare PV cell counts in MK801- and saline-treated male and female rats. The electrophysiological findings in females are reflected in behavioral performance on two tests of cognition. MK801-treated female rats show impairments in working memory and cognitive flexibility compared to saline-treated controls, and performance improves when PV cell activity is increased. Specifically, a two-way mixed ANOVA of T-maze performance showed a significant main effect of group. As expected, the SZ model group performed significantly worse than the control group. Interestingly, the rescue group’s performance was not significantly different from the control group. A mixed two-way ANOVA analysis of the set shifting task showed significant main effects of group on rule acquisition. The SZ model group required more trials to learn the rules than controls. The rescue group acquired the task significantly faster than the SZ model group and was not significantly different from controls. When looking at the types of errors made, we see that the SZ model animals made more perseverative errors than both controls and rescue group animals, while rescue and control animals performed similarly.
Discussion
The partial rescue of working memory and the robust rescue of cognitive flexibility we observe suggest that upregulating the activity of PV interneurons that remain in SZ may works as a strategy for ameliorating prefrontal GABAergic deficits and cognitive impairments. This study examines the mechanisms underlying cognitive dysfunction in SZ, potentially pointing to effective novel therapeutics. We have validated the effectiveness of our rescue across cellular, electrophysiological, and behavioral dimensions. Future directions include further exploration of gender differences including adjustments to our MK801 model that may elicit E/I deficits in males.
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Details
- Title
- F22. UPREGULATING A REDUCED POPULATION OF PREFRONTAL PARVALBUMIN INTERNEURONS TO RESTORE COGNITIVE FUNCTION IN SCHIZOPHRENIA
- Creators
- Linda Chamberlin - Drexel UniversityBrielle Ferguson - Stanford UniversityErin McEachern - Drexel UniversityBasant Nassar - Drexel UniversityWen-Jun Gao - Drexel University
- Publication Details
- Schizophrenia bulletin, Vol.45(Supplement_2), pp.S262-S263
- Publisher
- Oxford University Press
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Identifiers
- 991019167602404721
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- Domestic collaboration
- Web of Science research areas
- Psychiatry