title: 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. We developed 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 or ABT-418, an α4β2nicotinic acetylcholine receptor (nAChR) agonist, normalized MSO task performance in ketamine-treated rats and this effect was blocked by GABAAreceptor antagonism. GABAergic currents were also decreased in OFC of ketamine-treated rats and were normalized by activation of α4β2nAChRs. 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 α4β2nAChRs. 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.
  
  
  
  Adaptive behaviors are driven by integration of information from different sensory modalities. Multisensory integration is disrupted in patients with schizophrenia, but little is known about the neural basis of this cognitive symptom. Development and validation of multisensory integration tasks for animal models is essential given the strong link between functional outcome and cognitive impairment in schizophrenia. We present a novel multisensory object oddity procedure that detects selective multisensory integration deficits in a rat model of schizophrenia using various combinations of sensory modalities. Moreover, converging data are consistent with a nicotinic-GABAergic mechanism of multisensory integration in the prefrontal cortex, results with strong clinical relevance to the study of cognitive impairment and treatment in schizophrenia.
authors.affiliation: Department of Psychology.|Collabrative Neuroscience Program, and.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Cloke
authors.affiliation: Department of Psychology, University of Toronto, Toronto, Ontario, Canada M5S 3GS.
authors.forename: Robin
authors.initials: R
authors.lastname: Nguyen
authors.affiliation: Collabrative Neuroscience Program, and.|Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1, and.
authors.forename: Beryl Y T
authors.identifier: 0000-0002-2198-3937
authors.initials: BY
authors.lastname: Chung
authors.affiliation: Department of Psychology.
authors.forename: David I
authors.initials: DI
authors.lastname: Wasserman
authors.affiliation: Department of Psychology.
authors.forename: Stephanie
authors.initials: S
authors.lastname: De Lisio
authors.affiliation: Department of Psychology, University of Toronto, Toronto, Ontario, Canada M5S 3GS.
authors.forename: Jun Chul
authors.identifier: 0000-0001-9920-3307
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Collabrative Neuroscience Program, and.|Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1, and.
authors.forename: Craig D C
authors.identifier: 0000-0002-4320-6872
authors.initials: CD
authors.lastname: Bailey
authors.affiliation: Department of Psychology, bwinters@uoguelph.ca.|Collabrative Neuroscience Program, and.
authors.forename: Boyer D
authors.initials: BD
authors.lastname: Winters
mesh_terms: D000818:Animals; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D007649:Ketamine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018722:Nicotinic Agonists / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012559:Schizophrenia / Q000139:chemically induced; D012565:Schizophrenic Psychology; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D007555:Isoxazoles; D018722:Nicotinic Agonists; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D005680:gamma-Aminobutyric Acid; D007649:Ketamine
keywords: DREADDs; ketamine; multisensory integration; nicotine; object perception; rats