Activity‐dependent downregulation of D‐type K⁺ channel subunit Kv1.2 in rat hippocampal CA3 pyramidal neurons

Abstract

Key points• The intrinsic excitability of a hippocampal CA3 pyramidal cell (CA3-PC), but not CA1-PC, is enhanced by repetitive somatic firing at a physiologically relevant frequency (10 Hz for 2 s).• Such an excitability change is mediated by the Ca 2+ -and Src family kinase-dependent endocytosis of D-type K + channel subunit Kv1.2.• We provide evidence that the surface expression of D-type K + channels is higher in the distal apical dendrites than in the proximal apical dendrites in CA3-PCs.• These results help us understand neuronal computational mechanisms underlying the cognitive functions of the hippocampal CA3 area.Abstract The intrinsic excitability of neurons plays a critical role in the encoding of memory at Hebbian synapses and in the coupling of synaptic inputs to spike generation. It has not been studied whether somatic firing at a physiologically relevant frequency can induce intrinsic plasticity in hippocampal CA3 pyramidal cells (CA3-PCs). Here, we show that a conditioning train of 20 action potentials (APs) at 10 Hz causes a persistent reduction in the input conductance and an acceleration of the AP onset time in CA3-PCs, but not in CA1-PCs. Induction of such long-term potentiation of intrinsic excitability (LTP-IE) was accompanied by a reduction in the D-type K + current, and was abolished by the inhibition of endocytosis or protein tyrosine kinase (PTK). Consistently, the CA3-PCs from Kv1.2 knock-out mice displayed no LTP-IE with the same conditioning. Furthermore, the induction of LTP-IE depended on the back-propagating APs (bAPs) and intact distal apical dendrites. These results indicate that LTP-IE is mediated by the internalization of Kv1.2 channels from the distal regions of apical dendrites, which is triggered by bAP-induced dendritic Ca 2+ signalling and the consequent activation of PTK.

Adrenergic Gate Release for Spike Timing-Dependent Synaptic Potentiation

“…1, 2). The contribution of dendritic Kv1.1 to I D is in agreement with previous studies, showing an attribution of other paralogs of the Kv1 family, such as dendritic Kv1.2, to I D in other cortical neurons (Bekkers and Delaney, 2001; Hyun et al, 2013). …”

Genetic perturbations suggest a role of the resting potential in regulating the expression of the ion channels of the KCNA and HCN families in octopus cells of the ventral cochlear nucleus

“…When the glycosylation sites were removed, surface expression of Kv1.2, Kv1.3 and Kv1.4 decreased but expression of Kv1.1 was unaffected (Watanabe et al, 2015; Watanabe et al, 2007; Watanabe et al, 2004; Thayer et al, 2016). In hippocampal pyramidal cells, DTX-sensitive currents mediated by channels that contain Kv1.2 are also regulated by electrical activity through Ca 2+ entry (Hyun et al, 2013). It has also been reported that cerebellar basket cells of heterozygotes that carry a mutation in Kv1.1, Kcna1 V408A/+ , have normal somatic action potentials but broadened action potentials at terminals that resulted in an increased release of GABA that was not compensated (Begum et al, 2016).…”

Differential effects of static and dynamic inputs on neuronal excitability

“…A-type K channels containing subunits of the Kv4 and Kv1 families regulate the repetitive firing and spike timing in cortical neurons (Carrasquillo et al 2012;Hyun et al 2013;Jung and Hoffman 2009). They have been shown to undergo activitydependent changes that manifest as a form of long-term potentiation of intrinsic excitability (Francesconi et al 2009;Hyun et al 2013), so they can contribute to the maintenance of excitatory-inhibitory balance in neural circuits (Campanac et al 2013). Inward rectifying K channels also delay the spike responses of neurons under depolarizing inputs, but their role is more significant in setting the resting membrane potential and input resistance of cells (Young et al 2009).…”

“…Neuronal output is therefore produced by a complex interplay between the synaptic inputs and the voltage-dependent membrane conductances. An increasing number of studies demonstrate that intrinsic cellular properties of neurons are subject to activitydependent plastic changes and homeostatic regulation similarly to those of synaptic properties (Hyun et al 2013;Jung and Hoffman 2009;O'Leary et al 2010;van Welie et al 2004). In this respect, learning, memory, and various other forms of activity-dependent plasticity are also strongly linked to intrinsic excitability and the operation of the voltage-gated channels (Desai et al 1999;Schulz 2006;Turrigiano 2011).…”