Ngodup Tenzin, Irie Tomohiko, Elkins Sean, Trussell Laurence O
Oregon Hearing Research Center and Vollum Institute, Oregon Health & Science University, Portland OR USA.
Department of Physiology, Kitasato University School of Medicine, Sagamihara, Japan.
bioRxiv. 2023 Nov 8:2023.06.23.546323. doi: 10.1101/2023.06.23.546323.
Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multisensory 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, 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. GABA 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.
耳蜗背核（DCN）的车轮状中间神经元能有效抑制与初级听觉传入输入汇聚的多感觉信号，从而调节听觉处理。来自蓝斑的去甲肾上腺素能纤维投射到DCN，α2-肾上腺素能受体抑制自发放电活动，但同时增强车轮状细胞的突触强度，这种双重作用导致抑制作用的信噪比提高。然而，这种显著调制的离子机制尚不清楚。我们构建了甘氨酸能神经元特异性敲除钠渗漏通道NALCN的模型，发现车轮状细胞的自发放电需要该通道的存在。α2-肾上腺素能受体的激活抑制了NALCN和动作电位的产生，而这种调制在NALCN敲除模型中不存在。此外，敲除模型中也不存在α2依赖性的突触强度增强。GABA受体也通过NALCN介导抑制作用，作用于与α2受体相同的通道群体，这表明两种受体亚型与NALCN紧密相邻。因此，多个神经调节系统通过抑制兴奋性渗漏通道NALCN来决定突触抑制的影响。
