TY - JOUR
T1 - The Na+ leak channel NALCN controls spontaneous activity and mediates synaptic modulation by α2-adrenergic receptors in auditory neurons
AU - Ngodup, Tenzin
AU - Irie, Tomohiko
AU - Elkins, Seán P.
AU - Trussell, Laurence O.
N1 - Publisher Copyright:
© Ngodup, Irie et al.
PY - 2024
Y1 - 2024
N2 - Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multi-sensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. Noradrenergic fibers from locus coeruleus project to the DCN, and α2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal-to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na+ leak channel NALCN in mice and found that its presence was required for spontaneous firing in cartwheel cells. Activation of α2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, α2-dependent enhancement of synaptic strength was also absent in the knockout. GABAB receptors mediated inhibition through NALCN as well, acting on the same population of channels as α2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN.
AB - Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multi-sensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. Noradrenergic fibers from locus coeruleus project to the DCN, and α2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal-to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na+ leak channel NALCN in mice and found that its presence was required for spontaneous firing in cartwheel cells. Activation of α2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, α2-dependent enhancement of synaptic strength was also absent in the knockout. GABAB receptors mediated inhibition through NALCN as well, acting on the same population of channels as α2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN.
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U2 - 10.7554/eLife.89520
DO - 10.7554/eLife.89520
M3 - Article
C2 - 38197879
AN - SCOPUS:85182086625
SN - 2050-084X
VL - 13
JO - eLife
JF - eLife
M1 - RP89520
ER -