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Multisensory Integration Impairment in Rodent Models of Schizophrenia: Converging Evidence for Remediation by Nicotinic Receptor Stimulation of the GABAergic System

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Title: Multisensory Integration Impairment in Rodent Models of Schizophrenia: Converging Evidence for Remediation by Nicotinic Receptor Stimulation of the GABAergic System
Author: Cloke, Jacob
Department: Department of Psychology
Program: Psychology
Advisor: Winters, Boyer
Abstract: This thesis investigated the selective multisensory integration impairment in ketamine-treated rats, a rodent model of schizophrenia. Previous findings have shown that ketamine-treated rats are impaired on a crossmodal object recognition (CMOR) task, but not on similar tests that do not require multisensory binding. In the current thesis, this effect was replicated and extended using a novel multisensory object oddity (MSO) task, which directly assesses multisensory binding in the absence of significant memory demands; ketamine-treated rats were impaired on tactile-visual and olfactory-visual MSO, but not on similar unimodal oddity tasks. Systemic administration of nicotine reversed the CMOR and MSO impairments in ketamine-treated rats. This effect appears to be mediated by α4β2 nicotinic acetylcholine receptors (nAChR), as the selective α4β2 agonist ABT-418, but not the selective α7 nAChR agonist GTS-21, restored CMOR and MSO performance in ketamine-treated rats. The involvement of nAChRs in remediating this cognitive impairment was explored in the orbitofrontal (OFC) and medial prefrontal (mPFC) cortices. Intra-OFC, but not intra-mPFC, ABT-418 restored multisensory cognition in ketamine-treated rats. Prompted by past research indicating dysfunctional GABAergic transmission in schizophrenia and ketamine-treated rats, we hypothesized that decreased OFC GABAergic function disrupts multisensory cognition and that OFC nAChRs restore performance in ketamine-treated rats by enhancing GABAergic release. Accordingly, the GABAA antagonist bicuculline blocked the remediating effect of intra-OFC ABT-418 on CMOR and MSO performance. Additionally, whole-cell electrophysiology revealed disrupted GABAergic transmission in the OFC of ketamine-treated rats, and activation of α4β2 nAChRs restored GABAergic function. Moreover, immunohistochemical analyses indicated that GABAergic parvalbumin (PV)-interneuron (PV-IN) expression was decreased in the OFC of ketamine-treated rats. Thus, DREADDS (Designer Receptors Exclusively Activated by Designer Drugs) were used to silence OFC PV-INs in PV-Cre mice, revealing a selective MSO deficit that could be reversed by ABT-418. This thesis therefore proposes that dysfunction of OFC PV-INs in ketamine-treated rats causes their multisensory impairment and that activation of α4β2 nAChR on PV-INs restores essential inhibitory transmission reversing the multisensory deficit. Given the parallels between schizophrenia and the current rodent model, pharmacological therapies targeting the GABAergic system and/or GABAergic-nicotinic interactions hold promise for treating specific cognitive symptoms in schizophrenia.
Date: 2016
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