Sack Anne-Sophie, Garcia Esperanza, Snutch Terrance P
Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
eNeuro. 2025 Apr 4;12(4). doi: 10.1523/ENEURO.0423-24.2025. Print 2025 Apr.
T-Type calcium channels shape neuronal excitability driving burst firing, plasticity, and neuronal oscillations that influence circuit activity. The three biophysically distinct T-type channel subtypes (Cav3.1, Cav3.2, Cav3.3) are differentially expressed in the brain, contributing to divergent physiological processes. Cav3.2 channels are highly expressed in the dentate gyrus (DG) of the hippocampus, and mice lacking Cav3.2 [knock-out (KO)] exhibit impairments in hippocampal dependent learning and memory tasks, as well as attenuated development of pilocarpine induced epilepsy. Owing to neurogenesis, granule cells (GCs) are continuously added to the DG, generating a heterogeneous population of maturational stages with distinct excitability. While initial studies identified the role of Cav3.2 in mature GC burst firing, its functional relevance in the intrinsic excitability of different GC subpopulations has not yet been examined. In this study, we used juvenile Cav3.2 KO mice to examine the contributions of Cav3.2 channels to GC excitability at three different stages of maturation. We recorded from cells throughout the GC layer using their electrophysiological and morphological features to allocate GCs into immature, intermediate, and mature groups. In immature GCs, loss of Cav3.2 channels reduced the proportion of cells that fired low-threshold calcium spikes. Conversely, Cav3.2 KO increased excitability in regular spiking intermediate and mature GCs, enabling higher-frequency firing, with little impact on the frequency-dependent response. Overall, this study shows that Cav3.2 channels differentially regulate GC excitability throughout maturation and suggest that calcium influx via Cav3.2 may have maturation-dependent contributions to DG processes such as GC survival, integration, and memory encoding.
T型钙通道塑造神经元兴奋性,驱动爆发式放电、可塑性以及影响回路活动的神经元振荡。三种生物物理特性不同的T型通道亚型(Cav3.1、Cav3.2、Cav3.3)在大脑中差异表达,参与不同的生理过程。Cav3.2通道在海马齿状回(DG)中高度表达,缺乏Cav3.2的小鼠[基因敲除(KO)]在依赖海马的学习和记忆任务中表现出障碍,以及毛果芸香碱诱导的癫痫发育减弱。由于神经发生,颗粒细胞(GCs)不断添加到DG中,产生具有不同兴奋性的成熟阶段异质群体。虽然最初的研究确定了Cav3.2在成熟GC爆发式放电中的作用,但其在不同GC亚群固有兴奋性中的功能相关性尚未得到研究。在本研究中,我们使用幼年Cav3.2基因敲除小鼠来研究Cav3.2通道在成熟三个不同阶段对GC兴奋性的贡献。我们利用其电生理和形态学特征记录整个GC层的细胞,将GCs分为未成熟、中间和成熟组。在未成熟的GCs中,Cav3.2通道的缺失降低了触发低阈值钙尖峰的细胞比例。相反,Cav3.2基因敲除增加了规则发放的中间和成熟GCs的兴奋性,使其能够更高频率地放电,对频率依赖性反应影响很小。总体而言,本研究表明Cav3.2通道在整个成熟过程中差异调节GC兴奋性,并表明通过Cav3.2的钙内流可能对DG过程如GC存活、整合和记忆编码有成熟依赖性贡献。
Neuropharmacology. 2018-3-23
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