Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; Division of Neurology and CHOP Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Neuropharmacology. 2023 Mar 15;226:109400. doi: 10.1016/j.neuropharm.2022.109400. Epub 2022 Dec 29.
The dorsal subiculum (dSub) is one of the key structures responsible for the formation of hippocampal memory traces but the contribution of individual ionic currents to its cognitive function is not well studied. Although we recently reported that low-voltage-activated T-type calcium channels (T-channels) are crucial for the burst firing pattern regulation in the dSub pyramidal neurons, their potential role in learning and memory remains unclear. Here we used in vivo local field potential recordings and miniscope calcium imaging in freely behaving mice coupled with pharmacological and genetic tools to address this gap in knowledge. We show that the Ca3.1 isoform of T-channels is critically involved in controlling neuronal activity in the dSub in vivo. Altering neuronal excitability by inhibiting T-channel activity markedly affects calcium dynamics, synaptic plasticity, neuronal oscillations and phase-amplitude coupling in the dSub, thereby disrupting spatial learning. These results provide an important causative link between the Ca3.1 channels, burst firing of dSub neurons and memory formation, thus further supporting the notion that changes in neuronal excitability regulate memory processing. We posit that subicular Ca3.1 T-channels could be a promising novel drug target for cognitive disorders.
背侧下托（dSub）是负责海马记忆痕迹形成的关键结构之一，但个体离子电流对其认知功能的贡献尚未得到很好的研究。虽然我们最近报道了低电压激活的 T 型钙通道（T 通道）对于 dSub 锥体神经元爆发式放电模式的调节至关重要，但它们在学习和记忆中的潜在作用仍不清楚。在这里，我们使用了在自由活动的小鼠中进行的体内局部场电位记录和微镜钙成像，并结合药理学和遗传学工具来解决这一知识空白。我们表明，T 通道的 Ca3.1 同工型对于控制体内 dSub 中的神经元活动至关重要。通过抑制 T 通道活性改变神经元兴奋性，会显著影响 dSub 中的钙动力学、突触可塑性、神经元振荡和相位-幅度耦合，从而破坏空间学习。这些结果在 Ca3.1 通道、dSub 神经元爆发式放电和记忆形成之间提供了一个重要的因果联系，从而进一步支持了神经元兴奋性变化调节记忆处理的观点。我们假设，海马 Ca3.1 T 通道可能是认知障碍的一个有前途的新型药物靶点。
