Transient Potassium Channels: Therapeutic Targets for Brain Disorders

Transient potassium current channels (I_A channels), which are expressed in most brain areas, have a central role in modulating feedforward and feedback inhibition along the dendroaxonic axis. Loss of the modulatory channels is tightly associated with a number of brain diseases such as Alzheimer’s disease, epilepsy, fragile X syndrome (FXS), Parkinson’s disease, chronic pain, tinnitus, and ataxia. However, the functional significance of I_A channels in these diseases has so far been underestimated. In this review, we discuss the distribution and function of I_A channels. Particularly, we posit that downregulation of I_A channels results in neuronal (mostly dendritic) hyperexcitability accompanied by the imbalanced excitation and inhibition ratio in the brain’s networks, eventually causing the brain diseases. Finally, we propose a potential therapeutic target: the enhanced action of I_A channels to counteract Ca²⁺-permeable channels including NMDA receptors could be harnessed to restore dendritic excitability, leading to a balanced neuronal state.