Investigating brain network deficits in a rodent schizophrenia model

Schizophrenia is a chronic heterogenous neuropsychiatric disorder, yet the pathophysiological mechanisms leading to overt symptoms and deficits in cognition in schizophrenia remain largely unknown. Disrupted oscillatory activity in the gamma frequency in the prefrontal cortex and hippocampal neural networks is a core mechanism underlying cognitive impairment in the disorder. High-frequency gamma oscillations are generated by networks of interconnected gamma-aminobutyric acid interneurons both within and between the prefrontal cortex and the hippocampus. Fast-spiking, parvalbumin expressing interneurons in particular underlie these gamma oscillations, with a family of voltage-gated potassium channels, Kv3-type channels (Kv3.-Kv3.4) contributing to the high frequency firing of these interneurons. The aim of this project was to investigate in vivo whether deletion of Kv3 subunits expressed on fast-spiking, parvalbumin-expressing GABAergic interneurons in the medial prefrontal cortex and the hippocampus decreased neuronal activity. We performed extracellular recordings in the medial prefrontal cortex or hippocampus of awake, head-fixed mice lacking either KCNC1 gene encoding Kv3.1 channels or KCNC3 gene encoding Kv3.3 channels. Deficits in a number of neuronal activity measures were found in the medial prefrontal cortex and hippocampus of Kv3.1KO mice and Kv3.3KO mice. To investigate the effect of Kv3 subunit deletion on hippocampus-mPFC synchrony, simultaneous recordings were performed from the mPFC and hippocampus of awake, head-fixed Kv3.1KO mice and Kv3.3KO mice. Impaired synchrony between the medial prefrontal cortex and the hippocampus was found in a number of measures in the low frequency bands and an increased synchrony in the high frequency bands in Kv3.1KO mice and Kv3.3KO mice. Future studies could incorporate simultaneous neural recordings and behavioural tests to investigate the effect of dysfunctional neuronal activity we report here following Kv3 subunit deletion on cognitive functioning.