Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia.
Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia
J Neurosci. 2021 May 19;41(20):4392-4409. doi: 10.1523/JNEUROSCI.0967-20.2021. Epub 2021 Apr 13.
The molecular mechanisms tuning cholinergic interneuron (CIN) activity, although crucial for striatal function and behavior, remain largely unexplored. Previous studies report that the Etv1/Er81 transcription factor is vital for regulating neuronal maturation and activity. While Er81 is known to be expressed in the striatum during development, its specific role in defining CIN properties and the resulting consequences on striatal function is unknown. We report here that Er81 is expressed in CINs and its specific ablation leads to prominent changes in their molecular, morphologic, and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further reveal that Er81 expression is required for normal CIN pause and time-locked responses to sensorimotor inputs in awake mice. Overall, this study uncovers a new cell type-specific control of CIN function in the striatum which drives habit formation in adult male mice. Although previous studies have shown that cholinergic interneurons drive striatal activity and habit formation, the underlying molecular mechanisms controlling their function are unknown. Here we reveal that key cholinergic interneuron physiological properties are controlled by Er81, a transcription factor regulating neuronal activity and development in a cell-specific manner. Moreover, our findings uncover a link between the Er81-dependent molecular control of cholinergic interneuron function and habit formation in mice. These insights will contribute to the future enhancement of our understanding of disorders that involve behavioral inflexibility, such as autism and addiction.
尽管调节胆碱能中间神经元 (CIN) 活性的分子机制对纹状体功能和行为至关重要，但它们在很大程度上仍未得到探索。先前的研究报告称，Etv1/Er81 转录因子对于调节神经元成熟和活性至关重要。虽然已知 Er81 在发育过程中在纹状体中表达，但它在定义 CIN 特性及其对纹状体功能的影响方面的具体作用尚不清楚。我们在这里报告称，Er81 在 CIN 中表达，其特异性缺失会导致其分子、形态和电生理特征发生显著变化。特别是，Er81 的缺失会放大内在的延迟整流和超极化激活电流，从而改变 CIN 的紧张和相位活动。我们进一步揭示，Er81 表达对于正常的 CIN 暂停和在清醒小鼠中对感觉运动输入的时间锁定反应是必需的。总的来说，这项研究揭示了纹状体中 CIN 功能的一种新的细胞类型特异性控制，这种控制驱动成年雄性小鼠的习惯形成。尽管先前的研究表明胆碱能中间神经元驱动纹状体活动和习惯形成，但控制其功能的潜在分子机制尚不清楚。在这里，我们揭示了关键的胆碱能中间神经元生理特性受 Er81 控制，Er81 以细胞特异性的方式调节神经元的活性和发育。此外，我们的发现揭示了 Er81 依赖性的胆碱能中间神经元功能的分子控制与小鼠习惯形成之间的联系。这些见解将有助于未来增强我们对涉及行为灵活性障碍的疾病的理解，如自闭症和成瘾。
