Cerebellar Stellate Cell Excitability Is Coordinated by Shifts in the Gating Behavior of Voltage-Gated Na⁺and A-Type K⁺Channels

Abstract

Neuronal excitability in the vertebrate brain is governed by the coordinated activity of both ligand- and voltage-gated ion channels. In the cerebellum, spontaneous action potential (AP) firing of inhibitory stellate cells (SCs) is variable, typically operating within the 5- to 30-Hz frequency range. AP frequency is shaped by the activity of somatodendritic A-type K + channels and the inhibitory effect of GABAergic transmission. An added complication, however, is that whole-cell recording from SCs induces a time-dependent and sustained increase in membrane excitability making it difficult to define the full range of firing rates. Here, we show that whole-cell recording in cerebellar SCs of both male and female mice augments firing rates by reducing the membrane potential at which APs are initiated. AP threshold is lowered due to a hyperpolarizing shift in the gating behavior of voltage-gated Na + channels. Whole-cell recording also elicits a hyperpolarizing shift in the gating behavior of A-type K + channels which contributes to increased firing rates. Hodgkin–Huxley modeling and pharmacological experiments reveal that gating shifts in A-type K + channel activity do not impact AP threshold, but rather promote channel inactivation which removes restraint on the upper limit of firing rates. Taken together, our work reveals an unappreciated impact of voltage-gated Na + channels that work in coordination with A-type K + channels to regulate the firing frequency of cerebellar SCs.

Nitric Oxide Signaling Strengthens Inhibitory Synapses of Cerebellar Molecular Layer Interneurons through a GABARAP-Dependent Mechanism

“…Together, these observations suggest that NMDARs expressed by MLIs fulfill multiple functions that control the excitability of MLIs while impacting the physiological state of the surrounding cells and tissue. In keeping with this, unpublished data from our laboratory reveals that NMDARs also directly modulate MLI excitability (RPD Alexander and D. Bowie, unpublished observation) through a signaling pathway that leads to a hyperpolarizing shift in sodium channel (Nav) activation and inactivation recently described (Alexander et al, 2019). Interestingly, this pathway does not involve PKC but instead signals through the actions of CaMKII (Alexander and Bowie, unpublished observation) suggesting that Ca 21 influx through NMDARs in MLIs triggers a bifurcating pathway involving both CaMKII and nNOS.…”

Diverse Neuron Properties and Complex Network Dynamics in the Cerebellar Cortical Inhibitory Circuit

“…The excitability of BCs and SCs is shown to be modulated by several molecular mechanisms. For example, the firing rate of SCs is dynamically regulated by T-type channel-mediated Ca 2+ transient through A-type K + channel modulation (Molineux et al, 2005; Anderson et al, 2013; Alexander et al, 2019). Moreover, ML interneurons firing patterns are typically irregular, characterized by a shift toward a more regular rate when inhibitory synaptic currents are blocked (Figure 4C; Hausser and Clark, 1997; Lachamp et al, 2009).…”

Stellate cell computational modelling predicts signal filtering in the molecular layer circuit of cerebellum

“…SCs fire spontaneously in the 1-35 Hz range, both in vitro and in vivo (Llano and Gerschenfeld, 1993;Hausser and Clark, 1997;Carter and Regehr, 2002;Jorntell and Ekerot, 2002; Barmack and Yakhnitsa, 2008). The firing rate is dynamically regulated by several ionic channels, including Ttype Ca 2+ channels and A-type K + channels (Molineux et al, 2005;Anderson et al, 2013;Alexander et al, 2019). Evidence has also been provided about the receptors and currents involved in synaptic transmission (Astori and Köhr, 2008).…”