AUT00206, a novel and selective Kv3.1/3.2 channel modulator, restores cognitive dysfunction and negative symptoms in an animal model for schizophrenia symptomatology
Marianne Leger, Daniela Cadinu, Jennifer Fletcher, Agostino Marasco, Giuseppe Alvaro, Daniel Umbricht, Charles Large, Ben Grayson, Joanna C. Neill, Michael K. HarteBackground:
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.