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 ␣ 4 ␤ 2 nicotinic acetylcholine receptor (nAChR) agonist, normalized MSO task performance in ketamine-treated rats and this effect was blocked by GABA A receptor antagonism. GABAergic currents were also decreased in OFC of ketamine-treated rats and were normalized by activation of ␣ 4 ␤ 2 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 ␣ 4 ␤ 2 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.

Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms

“…Similarly, acute MK-801-induced memory impairments in mice are improved by acute nicotine administration [189], while chronic nicotine reverses heightened impulsivity in a mouse chronic PCP model [190]. Finally, systemic and intra-orbitofrontal cortex administration of nicotine or the nAChR agonist ABT-418 dose-dependently ameliorates chronic ketamine-induced impairments in a multisensory integration task, and this effect is blocked by GABA-A receptor antagonism [191]. These effects appear dependent on parvalbumin interneurons in the orbitofrontal cortex, as silencing parvalbumin interneurons impairs multisensory integration task performance, and this is reversed by ABT-418 administration [191].…”

“…Finally, systemic and intra-orbitofrontal cortex administration of nicotine or the nAChR agonist ABT-418 dose-dependently ameliorates chronic ketamine-induced impairments in a multisensory integration task, and this effect is blocked by GABA-A receptor antagonism [191]. These effects appear dependent on parvalbumin interneurons in the orbitofrontal cortex, as silencing parvalbumin interneurons impairs multisensory integration task performance, and this is reversed by ABT-418 administration [191]. Collectively, this suggests acute and chronic nicotine can improve cognitive impairment in an MK-801 schizophrenia rodent model, an effect which may depend on parvalbumin interneuron function in the PFC.…”

T-type calcium channels in the orbitofrontal cortex mediate sensory integration as measured using a spontaneous oddity task in rats

“…Processing sensory information into contextually rich representations of the environment is fundamental to cognition. The ability of the brain to generate a coherent representation of reality by consolidating simultaneously experienced stimuli from the same or different modalities is termed sensory integration (SI) or multisensory integration (MSI), respectively (Stein and Stanford 2008;Cloke et al 2016). Cognitive abnormalities are characteristic symptoms of brain disorders such as schizophrenia, autism, and epilepsy (Caplan et al 2008;Keefe and Harvey 2012;Leekam 2016).…”

“…Indeed, MSI impairments are observed in neuropsychiatric populations (Oberman and Ramachandran 2008;Tseng et al 2015) and impaired SI of unimodal stimuli is also observed during some symptoms such as psychosis (Carter et al 2017). Despite the known deficits in MSI in human psychiatric populations, progress in this area has been hindered by a lack of valid behavioral assessments for animal models, particularly rodents (Cloke et al 2016). Considering the severity of cognitive symptoms in psychiatric illness correlate strongly with patient functional outcome (Tamminga et al 1998), the need for additional insight into the neural bases of MSI in both healthy and disease states is needed.…”

“…In particular, CMOR cannot assess MSI in the absence of mnemonic demand as there is a delay between an initial object exploration phase and object recognition phase that requires memory. A novel paradigm, the multisensory object oddity (MSO) task, improves upon the limitation of CMOR in this regard (Cloke et al 2016). Similar to CMOR and other spontaneous object recognition tasks, MSO exploits rodents' innate tendency to explore oddity and is advantageous in that it provides a nonaversive means of assessing MSI that does not require prior training (Winters et al 2008).…”