Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon 97239, USA.
J Neurosci. 2011 Feb 16;31(7):2638-48. doi: 10.1523/JNEUROSCI.6081-10.2011.
Premature and uncompensated loss of ovarian hormones following ovariectomy (OVX) elevates the risks of cognitive impairment and dementia. These risks are prevented with estrogen (E(2))-containing hormone replacement therapy initiated shortly following OVX but not after substantial delay. Currently, the cellular bases underlying these clinical findings are unknown. At the cellular level, intrinsic membrane properties regulate the efficiency of synaptic inputs to initiate output action potentials (APs), thereby affecting neuronal communication, hence cognitive processing. This study tested the hypothesis that in CA1 pyramidal neurons, intrinsic membrane properties and their acute regulation by E(2) require ovarian hormones for maintenance. Whole-cell current-clamp recordings were performed on neurons from ∼ 7-month-old OVX rats that experienced either short-term (10 d, control OVX) or long-term (5 months, OVX(LT)) ovarian hormone deficiency. The results reveal that long-term hormone deficiency reduced intrinsic membrane excitability (IE) as measured by the number of evoked APs and firing duration for a given current injection. This was accompanied by AP broadening, an increased slow afterhyperpolarization (sAHP), and faster accumulation of Na(V) channel inactivation during repetitive firing. In the control OVX neurons, E(2) acutely increased IE and reduced the sAHP. In contrast, acute regulation of IE by E(2) was absent in the OVX(LT) neurons. Since the degree of IE of hippocampal pyramidal neurons is positively related with hippocampus-dependent learning ability, and modulation of IE is observed following successful learning, these findings provide a framework for understanding hormone deficiency-related cognitive impairment and the critical window for therapy initiation.
卵巢切除（OVX）后卵巢激素的过早和未补偿性丧失会增加认知障碍和痴呆的风险。这种风险可以通过 OVX 后不久开始的含有雌激素（E(2)）的激素替代疗法来预防，但不能在大量延迟后预防。目前，这些临床发现的细胞基础尚不清楚。在细胞水平上，内在膜特性调节突触输入引发输出动作电位（AP）的效率，从而影响神经元通讯，进而影响认知处理。这项研究检验了以下假设：在 CA1 锥体神经元中，内在膜特性及其对 E(2)的急性调节需要卵巢激素来维持。对来自约 7 个月大的 OVX 大鼠的神经元进行全细胞电流钳记录，这些大鼠经历了短期（10 天，对照 OVX）或长期（5 个月，OVX(LT)）卵巢激素缺乏。结果表明，长期激素缺乏会降低内在膜兴奋性（IE），这可以通过引发的 AP 数量和给定电流注入的放电持续时间来衡量。这伴随着 AP 变宽、超极化缓慢后超极化（sAHP）增加以及在重复放电过程中 Na(V)通道失活的更快积累。在对照 OVX 神经元中，E(2)急性增加了 IE 并减少了 sAHP。相比之下，在 OVX(LT)神经元中，E(2)对 IE 的急性调节不存在。由于海马锥体神经元的 IE 程度与海马依赖的学习能力呈正相关，并且在成功学习后观察到 IE 的调节，因此这些发现为理解与激素缺乏相关的认知障碍和治疗开始的关键窗口期提供了一个框架。
