The Auxiliary Subunit KChIP2 Is an Essential Regulator of Homeostatic Excitability

The somatodendritic I-A (A-type) K+ current underlies neuronal excitability, and loss of I-A has been associated with the development of epilepsy. Whether any one of the four auxiliary potassium channel interacting proteins (KChIPs), KChIP1-KChIP4, in specific neuronal populations is critical for I-A is not known. Here we show that KChIP2, which is abundantly expressed in hippocampal pyramidal cells, is essential for I-A regulation in hippocampal neurons and that deletion of Kchip2 affects susceptibility to limbic seizures. The specific effects of Kchip2 deletion on I-A recorded from isolated hippocampal pyramidal neurons were a reduction in amplitude and shift in the V-1/2 for steady-state in activation to hyperpolarized potentials when compared with WT neurons. Consistent with the relative loss of I-A, hippocampal neurons from Kchip2(-/-) mice showed increased excitability. WT cultured neurons fired only occasional single action potentials, but the average spontaneous firing rate (spikes/s) was almost 10-fold greater in Kchip2(-/-) neurons. In slice preparations, spontaneous firing was detected in CA1 pyramidal neurons from Kchip2(-/-) mice but not from WT. Additionally, when seizures were induced by kindling, the number of stimulations required to evoke an initial class 4 or 5 seizure was decreased, and the average duration of electrographic seizures was longer in Kchip2(-/-) mice compared with WT controls. Together, these data demonstrate that the KChIP2 is essential for physiologic I-A modulation and homeostatic stability and that there is a lack of functional redundancy among the different KChIPs in hippocampal neurons.