Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
J Physiol. 2021 Jan;599(2):647-665. doi: 10.1113/JP280627. Epub 2020 Nov 16.
We show that NMDA receptors (NMDARs) elicit a long-term increase in the firing rates of inhibitory stellate cells of the cerebellum NMDARs induce intrinsic plasticity through a Ca - and CaMKII-dependent pathway that drives shifts in the activation and inactivation properties of voltage-gated Na (Na ) channels An identical Ca - and CaMKII-dependent signalling pathway is triggered during whole-cell recording which lowers the action potential threshold by causing a hyperpolarizing shift in the gating properties of Na channels. Our findings open the more general possibility that NMDAR-mediated intrinsic plasticity found in other cerebellar neurons may involve similar shifts in Na channel gating.
Memory storage in the mammalian brain is mediated not only by long-lasting changes in the efficacy of neurotransmitter receptors but also by long-term modifications to the activity of voltage-gated ion channels. Activity-dependent plasticity of voltage-gated ion channels, or intrinsic plasticity, is found throughout the brain in virtually all neuronal types, including principal cells and interneurons. Although intrinsic plasticity has been identified in neurons of the cerebellum, it has yet to be studied in inhibitory cerebellar stellate cells of the molecular layer which regulate activity outflow from the cerebellar cortex by feedforward inhibition onto Purkinje cells. The study of intrinsic plasticity in stellate cells has been particularly challenging as membrane patch breakthrough in electrophysiology experiments unintentionally triggers changes in spontaneous firing rates. Using cell-attached patch recordings to avoid disruption, we show that activation of extrasynaptic N-methyl-d-aspartate receptors (NMDARs) elicits a long-term increase in the firing properties of stellate cells by stimulating a rise in cytosolic Ca and activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). An identical signalling pathway is triggered during whole-cell recording which lowers the action potential threshold by causing a hyperpolarizing shift in the gating properties of voltage-gated sodium (Na ) channels. Together, our findings identify an unappreciated role of Na channel-dependent intrinsic plasticity in cerebellar stellate cells which, in concert with non-canonical NMDAR signalling, provides the cerebellum with an unconventional mechanism to fine-tune motor behaviour.
我们表明，N-甲基-D-天冬氨酸受体（NMDAR）通过 Ca²⁺和 CaMKII 依赖性途径引发小脑抑制性星状细胞的放电率长期增加，该途径驱动电压门控 Na（Na⁺）通道的激活和失活特性发生变化。在全细胞记录期间触发相同的 Ca²⁺和 CaMKII 依赖性信号通路，通过引起 Na 通道门控特性的超极化偏移来降低动作电位阈值。通道。我们的发现使更一般的可能性成为可能，即在其他小脑神经元中发现的 NMDAR 介导的内在可塑性可能涉及 Na 通道门控的类似变化。
哺乳动物大脑中的记忆存储不仅通过神经递质受体效力的长期变化介导，而且还通过电压门控离子通道的长期修饰来介导。几乎所有神经元类型（包括主细胞和中间神经元）的大脑中都存在电压门控离子通道的活性依赖性可塑性或内在可塑性。尽管已经在小脑神经元中鉴定出了内在可塑性，但尚未在分子层的抑制性小脑星状细胞中进行研究，这些细胞通过对浦肯野细胞的前馈抑制来调节小脑皮层的活动输出。星状细胞的内在可塑性研究特别具有挑战性，因为在电生理学实验中膜片钳突破会无意中触发自发放电率的变化。使用细胞附着式膜片钳记录来避免中断，我们表明，通过刺激细胞浆 Ca²⁺升高和激活 Ca²⁺/钙调蛋白依赖性蛋白激酶 II（CaMKII），激活 extrasynaptic N-甲基-D-天冬氨酸受体（NMDAR）可引发星状细胞的放电特性长期增加。在全细胞记录期间触发相同的信号通路，通过引起电压门控钠（Na⁺）通道的门控特性超极化偏移来降低动作电位阈值。总之，我们的发现确定了小脑星状细胞中 Na 通道依赖性内在可塑性的未被认识的作用，与非典型 NMDAR 信号传导一起，为小脑提供了一种微调运动行为的非传统机制。
