Type I TARPs regulate Kv7.2 potassium channels and susceptibility to seizures

The M-current is a low-threshold potassium current that modulates neuronal excitability and suppresses repetitive firing. However, the mechanisms regulating M-channel function remain unclear. We identified type I Transmembrane AMPA receptor Regulatory Proteins (TARPs) as M-channel Kv7.2 subunit interactors in cortical neurons, with their interaction increasing upon neuronal depolarization. Co-expression of TARPs with Kv7.2 increased channel surface expression and Kv7.2-mediated currents, while disrupting TARP-γ2 expression in neurons perturbed dendritic Kv7.2 nano-clusters and decreased M-currents. Knock-in mice with an intellectual disability-associated TARP-γ2 variant showed reduced hippocampal M-currents and increased seizure susceptibility, indicating that disrupting TARP-γ2 regulation of Kv7.2-M-channels is epileptogenic. These findings show that TARP-γ2, a synaptic protein crucial for excitatory transmission, also controls intrinsic excitability via M-channels. This discovery provides a link between synaptic transmission and neuronal excitability, with implications for disease, as the interplay between synaptic and intrinsic plasticity is pivotal to how the brain adapts to varying input signals.