ATP‐sensitive K⁺ channels control the spontaneous firing of a glycinergic interneuron in the auditory brainstem

Abstract

Key points Cartwheel neurons provide potent inhibition to fusiform neurons in the dorsal cochlear nucleus (DCN). Most cartwheel neurons fire action potentials spontaneously, but the ion channels responsible for this intrinsic activity are unknown. We investigated the ion channels responsible for the intrinsic firing of cartwheel neurons and the stable resting membrane potential found in a fraction of these neurons (quiet neurons). Among the ion channels controlling membrane potential of cartwheel neurons, the presence of open ATP‐sensitive potassium channels (KATP) is responsible for the existence of quiet neurons. Our results pinpoint KATP channel modulation as a critical factor controlling the firing of cartwheel neurons. Hence, it is a crucial channel influencing the balance of excitation and inhibition in the DCN. Abstract Cartwheel neurons from the dorsal cochlear nucleus (DCN) are glycinergic interneurons and the primary source of inhibition on the fusiform neurons, the DCN's principal excitatory neuron. Most cartwheel neurons present spontaneous firing (active neurons), producing a steady inhibitory tone on fusiform neurons. In contrast, a small fraction of these neurons do not fire spontaneously (quiet neurons). Hyperactivity of fusiform neurons is seen in animals with behavioural evidence of tinnitus. Because of its relevance in controlling the excitability of fusiform neurons, we investigated the ion channels responsible for the spontaneous firing of cartwheel neurons in DCN slices from rats. We found that quiet neurons presented an outward conductance not seen in active neurons, which generates a stable resting potential. This current was sensitive to tolbutamide, an ATP‐sensitive potassium channel (KATP) antagonist. After inhibition with tolbutamide, quiet neurons start to fire spontaneously, while the active neurons were not affected. On the other hand, in active neurons, KATP agonist diazoxide activated a conductance similar to quiet neurons’ KATP conductance and stopped spontaneous firing. According to the effect of KATP channels on cartwheel neuron firing, glycinergic neurotransmission in DCN was increased by tolbutamide and decreased by diazoxide. Our results reveal a role of KATP channels in controlling the spontaneous firing of neurons not involved in fuel homeostasis.

Development of spontaneous firing of fusiform neurons from the dorsal cochlear nucleus of mice occurs after hearing onset

“…Correlation of activity threshold and postnatal days showed a significant negative correlation with age and a strong hyperpolarization of the activity threshold after P14 (Figure 2D). IV relationships of pre-hearing quiet neurons show that pre-hearing neurons have almost no inward deflection above -60 mV, produced by the development of I NaP (Leao et al ., 2012; Strazza et al ., 2021) (Figure 7Bi). The current at -55 mV is significantly bigger in pre-hearing neurons than in post-hearing quiet and active neurons (pre-quiet 106.33 ± 29.29 pA; post-quiet 39.99 ± 46.31 pA; active -85.35 ± 62.25 pA; one-way ANOVA: p<0.0001; pre-vs. post-quiet vs. active: p=0.028 and <0.0001; post-quiet vs. active: p=0.0006; Figura 7Bii, Table 1).…”

The potassium channels: Neurobiology and pharmacology of tinnitus

“…It is widely believed that hyperactivity of fusiform neurons is associated with tinnitus (Henton & Tzounopoulos, 2021; Wu et al., 2016). Based on the electrophysiological recordings from DCN slices from rats, inhibition of K ATP channels by tolbutamide causes quiet cartwheel neurons to start firing spontaneously and increases the frequency of glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs) on fusiform neurons, which produces an inhibitory effect on fusiform neurons and may be a new therapeutic target for tinnitus (Strazza et al., 2021). In contrast, salicylate in millimolar concentrations can activate K ATP channels in cartwheel neurons, leading to a reduction in spontaneous firing of cartwheel neurons and glycinergic neurotransmission on fusiform neurons, which contributes to the hyperactivity of fusiform neurons.…”