Abstract
The necessity for, or redundancy of, distinctive KChIP proteins is not known. Deletion of KChIP2 leads to increased susceptibility to epilepsy and to a reduction in IA and increased excitability in pyramidal hippocampal neurons. KChIP2 is essential for homeostasis in hippocampal neurons. Mutations in K(A) channel auxiliary subunits may be loci for epilepsy. The somatodendritic IA (A-type) K(+) current underlies neuronal excitability, and loss of IA 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 IA is not known. Here we show that KChIP2, which is abundantly expressed in hippocampal pyramidal cells, is essential for IA regulation in hippocampal neurons and that deletion of Kchip2 affects susceptibility to limbic seizures. The specific effects of Kchip2 deletion on IA recorded from isolated hippocampal pyramidal neurons were a reduction in amplitude and shift in the V½ for steady-state inactivation to hyperpolarized potentials when compared with WT neurons. Consistent with the relative loss of IA, 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 IA modulation and homeostatic stability and that there is a lack of functional redundancy among the different KChIPs in hippocampal neurons.
Highlights
The necessity for, or redundancy of, distinctive KChIP proteins is not known
As with deletion of Kv4.2, a chronic decrease in IA by KChIP2 deletion produced a compensatory up-regulation of inhibitory synaptic activity and a reduced excitatory input. We evaluated whether these homeostatic changes were present within the context of hippocampal brain slices, in which network architecture and intrinsic synaptic connections are preserved by recording sIPSCs and sEPSCs in CA1 pyramidal neurons
We found that in Kchip2Ϫ/Ϫ mice, the frequency (8 Ϯ 0.8 Hz versus 3 Ϯ 0.6 Hz; p ϭ 0.0003), amplitude (100 Ϯ 12.8 pA versus 65 Ϯ 4.6 pA; p ϭ 0.04), and amplitude distribution (p Ͻ 0.001) of sIPSCs increased in pyramidal neurons from Kchip2Ϫ/Ϫ mice (Fig. 7), consistent with what we observed in cultured hippocampal neurons (Fig. 6)
Summary
Results: Deletion of KChIP2 leads to increased susceptibility to epilepsy and to a reduction in IA and increased excitability in pyramidal hippocampal neurons. The specific effects of Kchip deletion on IA recorded from isolated hippocampal pyramidal neurons were a reduction in amplitude and shift in the V1⁄2 for steady-state inactivation to hyperpolarized potentials when compared with WT neurons. 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 IA modulation and homeostatic stability and that there is a lack of functional redundancy among the different KChIPs in hippocampal neurons. We evaluated the physiological consequences of KChIP2 deletion, considering the hypothesis that an effect on IA might influence the development of limbic seizures because of the importance of the hippocampus in networks involving limbic seizures
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