Prefrontal inhibition of neuronal Kv 7 channels enhances prepulse inhibition of acoustic startle reflex and resistance to hypofrontality

Background and purpose: Dysfunction of the prefrontal cortex (PFC) is involved in the cognitive deficits in neuropsychiatric diseases, such as schizophrenia, characterized by deficient neurotransmission known as NMDA Receptor hypofrontality. Thus, enhancing prefrontal activity may alleviate hypofrontality-induced cognitive deficits. To test this hypothesis, we investigated the effect of forebrain-specific suppression or pharmacological inhibition of native K_v 7/KCNQ/M-current on glutamatergic hypofrontality induced by the NMDA Receptor Antagonist MK-801.

Experimental approach: The forebrain-specific inhibition of native M-current was generated by transgenic expression, in mice, of a dominant-negative pore mutant G279S of K_v 7.2/KCNQ2 channels that suppresses channel function. A mouse model of cognitive impairment was established by single i.p. injection of 0.1 mg·kg^-1 MK-801. Mouse models of prepulse inhibition (PPI) of acoustic startle reflex and Y-maze spontaneous alternation test were used for evaluation of cognitive behaviour. Hippocampal brain slice recordings of LTP were used to assess synaptic plasticity. Hippocampus and cortex were dissected for detecting protein expression using western blot analysis.

Key results: Genetic suppression of K_v 7 channel function in the forebrain or pharmacological inhibition of K_v 7 channels by the specific blocker XE991 enhanced PPI and also alleviated MK-801 induced cognitive decline. XE991 also attenuated MK-801-induced LTP deficits and increased basal synaptic transmissions. Western blot analysis revealed that inhibiting K_v 7 channels resulted in elevation of pAkt1 and pGSK-3β expressions in both hippocampus and cortex.

Conclusions and implications: Both genetic and pharmacological inhibition of K_v 7 channels alleviated PPI and cognitive deficits. Mechanistically, inhibition of K_v 7 channels promotes synaptic transmission and activates Akt1/GSK-3β signalling.