3.3 Entraining Neural Networks Through Parvalbumin-Positive Interneurons: Can This Offer a Better way to Treat Schizophrenia?

Abstract

Background: Evidence supports a role of fast spiking GABAergic interneu-rons in the pathophysiology of schizophrenia. Dysfunction of these inter-neurons, which is associated with reductions in the calcium-binding protein, parvalbumin (PV), leads to disinhibition of cortical circuitry, dysregulation of gamma oscillations, and contributes to cognitive defcits in patients with schizophrenia. Kv3.1 potassium channels are selectively expressed by PV inter-neurons, where they permit accurate fring necessary to synchronize the fring of pyramidal neurons at gamma frequencies. Kv3.1 channels are reduced in unmedicated schizophrenia patients (Yanagi et al., 2014). Modulation of Kv3 may restore PV interneuron function in schizophrenia patients. This study describes a novel, frst-in-class Kv3 channel modulator, AUT00206, in rodent models and human tissue studies relevant to the symptoms of schizophrenia. Methods: Adult female rats received phencyclidine (scPCP) for 7 days followed by 6-week washout. Acute and chronic effcacy of AUT00206 in cognitive tests (novel object recognition and attentional set shifting) in these rats. Ex vivo electrophysiology studies using cortical slices from the rats and human cortical tissue from elective surgery examined network gamma activity. Additional studies examined the effects of AUT00206 after chronic treatment with antipsychotics (haloperidol or olanzapine). Results: AUT00206 signifcantly enhanced gamma oscillation power (26.1% ± 8.1%, n = 11, P