AUT00206, a novel and selective Kv3.1/3.2 channel modulator, restores cognitive dysfunction and negative symptoms in an animal model for schizophrenia symptomatology.

BACKGROUND: Voltage-gated Kv3.1 and KV3.2 potassium channels are mainly located on parvalbumin (PV) containing interneurons, where they play a key role in synchronising the coordinated firing of pyramidal neurons and regulating cognitive function. AIMS: We aim to explore the efficacy of acute treatment with AUT00206 (5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-me]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione), a novel and selective positive modulator of Kv3.1/3.2 channels, to improve cognitive and social behaviour deficits in our validated animal model relevant to schizophrenia. METHODS: Female Lister Hooded rats were treated with phencyclidine for 7 days, followed by a 7-day washout (scPCP). The efficacy of AUT00206 was tested in the novel object recognition (NOR), reversal learning (RL) and social interaction (SI) paradigms. RESULTS: The cognitive and social behaviour deficits induced by scPCP were significantly attenuated by AUT00206 (10 and 30 mg/kg) in the three behavioural tasks. These data demonstrate, for the first time, the efficacy of a novel Kv3.1/3.2 channel modulator, AUT00206, in two cognitive domains (short-term recognition memory and an aspect of cognitive flexibility) and an aspect of negative symptoms in a validated animal model of schizophrenia symptomatology. CONCLUSIONS: Modulation of Kv3.1/3.2 channels on PV interneurons could be an important novel approach for the treatment of schizophrenia.