A novel multisensory integration task reveals robust deficits in rodent models of schizophrenia: Converging evidence for remediation via nicotinic receptor stimulation of inhibitory transmission in the prefrontal cortex

Abstract

Atypical multisensory integration is an understudied cognitive symptom in schizophrenia. Procedures to evaluate multisensory integration in rodent models are lacking. Wedeveloped a novel multisensory object oddity (MSO) task to assess multisensory integration in ketamine-treated rats, a well established model of schizophrenia. Ketamine-treated rats displayed a selective MSO task impairment with tactile–visual and olfactory–visual sensory combinations, whereas basic unisensory perception was unaffected. Orbitofrontal cortex (OFC) administration of nicotine orABT-418, an α4β2 nicotinic acetylcholine receptor (nAChR)agonist, normalized MSO task performance in ketamine-treated ratsand this effect was blocked by GABAA receptor antagonism. GABA ergic currents were also decreased in OFC of ketamine-treated rats and were normalized by activation of α4β2 nAChRs. Furthermore, parvalbumin (PV) immunoreactivity was decreased in the OFC of ketamine-treated rats. Accordingly, silencing of PV interneurons in OFC of PV-Cre mice using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) selectively impaired MSO task performance and this was reversed by ABT-418. Likewise, clozapine-N-oxide-induced inhibition of PV interneurons in brain slices was reversed by activation of α4β2 nAChRs. These findings strongly imply a role for prefrontal GABAergic transmission in the integration of multisensory object features, a cognitive process with relevance to schizophrenia. Accordingly, nAChR agonism, which improves various facets of cognition in schizophrenia, reversed the severe MSO task impairment in this study and appears to do so via a GABAergic mechanism. Interactions between GABAergic and nAChR receptor systems warrant further investigation for potential therapeutic applications. The novel behavioral procedure introduced in the current study is acutely sensitive to schizophrenia-relevant cognitive impairment and should prove highly valuable for such research.