Kv4.1, a Key Ion Channel For Low Frequency Firing of Dentate Granule Cells, Is Crucial for Pattern Separation

Abstract

The dentate gyrus (DG) in the hippocampus may play key roles in remembering distinct episodes through pattern separation, which may be subserved by the sparse firing properties of granule cells (GCs) in the DG. Low intrinsic excitability is characteristic of mature GCs, but ion channel mechanisms are not fully understood. Here, we investigated ionic channel mechanisms for firing frequency regulation in hippocampal GCs using male and female mice, and identified Kv4.1 as a key player. Immunofluorescence analysis showed that Kv4.1 was preferentially expressed in the DG, and its expression level determined by Western blot analysis was higher at 8-week than 3-week-old mice, suggesting a developmental regulation of Kv4.1 expression. With respect to firing frequency, GCs are categorized into two distinctive groups: low-frequency (LF) and high-frequency (HF) firing GCs. Input resistance (R in) of most LF-GCs is lower than 200 M⍀, suggesting that LF-GCs are fully mature GCs. Kv4.1 channel inhibition by intracellular perfusion of Kv4.1 antibody increased firing rates and gain of the input-output relationship selectively in LF-GCs with no significant effect on resting membrane potential and R in , but had no effect in HF-GCs. Importantly, mature GCs from mice depleted of Kv4.1 transcripts in the DG showed increased firing frequency, and these mice showed an impairment in contextual discrimination task. Our findings suggest that Kv4.1 expression occurring at late stage of GC maturation is essential for low excitability of DG networks and thereby contributes to pattern separation.

Calbindin regulates Kv4.1 trafficking and excitability of dentate granule cells via CaMKII-dependent phosphorylation

“…The reduction in Iss (63%) was more pronounced than the reduction of Ipeak (36%). I4-AP in CBKO GCs was similar to I4-AP in the control GCs in the presence of Kv4.1 antibody, as reported previously (Kim et al, 2020). This suggests that the outward K + current component reduced in the CBKO GCs is likely to be the Kv4.1 current.…”

“…3A). ITEA obtained from CBKO GCs (n = 9) showed no significant difference compared to ITEA in control GCs reported previously (Kim et al, 2020) both with peak (Ipeak at +30 mV; 1.807 ± 0.152 nA, n = 9, for control; 1.727 ± 0.096 nA, n = 9, for CBKO, p = 0.66) and steady-state currents (Iss at +30 mV; 1.107 ± 0.126 nA, n = 9, for control: 1.012 ± 0.133 nA, n = 9, for CBKO, p = 0.609) (Figs. 3Bb, Bc).…”

“…3Ca), which are typical characteristics of A-type K + current, while that in the control GCs had a significant proportion of Iss, which is attributable to Kv4.1 current ( Fig. 3Cb) (Kim et al, 2020). The amplitude of I4-AP in CBKO GCs was significantly smaller than that in the control GCs (Figs.…”

“…The sparse activity of GCs has been regarded as essential for the computational function to accomplish pattern separation (O'Reilly and McClelland, 1994;Rolls, 2013;Treves and Rolls, 1994). We have recently discovered that Kv4.1 is a key ion channel for the low-frequency firing of GCs, and mice with Kv4.1 depletion in the DG show impaired pattern separation (Kim et al, 2020), highlighting the role of Kv4.1 in DG functions. It is intriguing to investigate the regulatory mechanisms of Kv4.1.…”

Kv1.2 contributes to pattern separation by regulating the hippocampal CA3 neuronal ensemble size

“…There were no changes in activity, feeding, reproductive, or parental behaviors in Kcna1+/− (n = 10) and Kcna2+/− (n = 9) mice, compared to WT (n = 11) mice. To examine behavioral pattern separation, the three genotype mice (WT littermates, Kcna1+/− and Kcna2+/− ) were subject to the contextual fear discrimination task (McHugh et al, 2007; Kim et al, 2020). This task is comprised of three phases: contextual acquisition phase (day 1-3), generalization test phase (day 4-5), and the discrimination training phase (day 6-14) (Figure 3A).…”