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

摘要

>Background: Evidence supports a role of fast spiking GABAergic interneurons in the pathophysiology of schizophrenia. Dysfunction of these interneurons, 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 deficits in patients with schizophrenia. Kv3.1 potassium channels are selectively expressed by PV interneurons, where they permit accurate firing necessary to synchronize the firing 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, first-in-class Kv3 channel modulator, , 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 efficacy of 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 after chronic treatment with antipsychotics (haloperidol or olanzapine). >Results: significantly enhanced gamma oscillation power (26.1% ± 8.1%, n = 11, P < .01) in prelimbic cortex and infralimbic cortex (19.7% ± 8.4%, n = 19, P < .05) of scPCP-treated rats, with no effect in slices from control animals. enhanced gamma oscillations by 40.4% ± 12.5 % (n = 3, ns) in human neocortical slices acutely pretreated with PCP but had no effect on oscillations in the absence PCP. Acute treatment with restored short-term memory deficits induced by scPCP alone and after chronic treatment with haloperidol (P < .05) or olanzapine (P < .05). scPCP treatment produced a selective deficit in the extradimensional shift phase of the ASST (P < .001) which was significantly attenuated by 14-day treatment with at 60 mg/kg (P < .001) alone or after haloperidol (P < .001). Twenty-one days of treatment with rescued the deficit in PV cell density in cortical and hippocampal brain slices (P < .05-.01). >Conclusion: enhanced gamma oscillations in cortex from scPCP-treated, but not normal rats, and slices acutely treated with PCP from humans, consistent with the modulation of Kv3 channels on PV neurons. In behavioral tests, rescued behavioral deficits in cognitive function in the absence or presence of antipsychotic treatment. Chronic dosing reversed the reduced PV cell density, consistent with an enhancement of PV-interneuron function. These results suggest a targeted means to rescue PV-interneuron function which may provide a novel approach to the treatment of schizophrenia.