Neuroscience Division, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
Biol Psychiatry. 2012 Sep 15;72(6):491-8. doi: 10.1016/j.biopsych.2012.03.016. Epub 2012 Apr 21.
Variations in maternal care in the rat associate with robust differences in hippocampal development and synaptic plasticity in the offspring. Maternal care also influences pituitary-adrenal stress responses and corticosterone (CORT) regulation of hippocampal plasticity. N-methyl-D-aspartate receptors (NMDAR) regulate synaptic plasticity, and NMDAR function is modulated by stress and CORT. We hypothesized that altered NMDAR function underlies the interaction of maternal and stress effects on hippocampal synaptic plasticity.
We used electrophysiology and western blot to examine NMDAR synaptic function/expression and NMDAR-dependent long-term potentiation (LTP) in adult offspring of mothers that varied in the frequency of pup licking/grooming (LG) (i.e., High or Low LG).
Basal NMDAR synaptic function was enhanced in the hippocampal dentate gyrus (DG) of adult Low LG offspring. Synaptic expression of NMDAR but not α-amino-3-hydroxy-methyl-4-isoxazole propionic acid receptors was also increased. Stress level CORT (100 nmol/L) rapidly (< 20 min) and robustly increased NMDAR function in High LG offspring, eliminating the maternal effect. Corticosterone did not affect NMDAR function in Low LG offspring. Bovine serum albumin-conjugated CORT reproduced the CORT effect in High LG offspring, implicating a membrane-bound corticosteroid receptor. NMDAR hyperfunction might impair synaptic plasticity. Partial NMDAR antagonism by low concentration DL-2-Amino-5-phosphonopentanoic acid rescued a basal LTP deficit in Low LG offspring and inhibited LTP in High LG offspring.
Low LG offspring exhibit basally elevated NMDAR function coupled with insensitivity to CORT modulation indicative of a chronic alteration of NMDAR function. Elevated NMDAR function in the hippocampus might underlie impaired LTP in Low LG offspring.
在老鼠中，母体照顾的变化与后代海马体发育和突触可塑性的显著差异有关。母体照顾还会影响垂体肾上腺应激反应和皮质酮（CORT）对海马体可塑性的调节。N-甲基-D-天冬氨酸受体（NMDAR）调节突触可塑性，NMDAR 功能受应激和 CORT 调节。我们假设，NMDAR 功能的改变是母体和应激对海马体突触可塑性相互作用的基础。
我们使用电生理学和 Western blot 技术，检测了母亲舔/梳理幼崽频率（高 LG 或低 LG）不同的成年后代的海马体齿状回（DG）中的 NMDAR 突触功能/表达和 NMDAR 依赖性长时程增强（LTP）。
低 LG 后代的海马体 DG 中的基础 NMDAR 突触功能增强。NMDAR 的突触表达增加，而 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPA）的表达没有增加。应激水平的皮质酮（100nmol/L）在高 LG 后代中迅速（<20 分钟）且强烈地增加了 NMDAR 功能，消除了母体效应。皮质酮对低 LG 后代的 NMDAR 功能没有影响。牛血清白蛋白结合的皮质酮复制了高 LG 后代的皮质酮效应，提示存在膜结合的皮质类固醇受体。NMDAR 过度功能可能会损害突触可塑性。低浓度的 DL-2-氨基-5-磷戊酸对 NMDAR 的部分拮抗作用，挽救了低 LG 后代的基础 LTP 缺陷，并抑制了高 LG 后代的 LTP。
低 LG 后代表现出基础 NMDAR 功能升高，同时对 CORT 调节不敏感，表明 NMDAR 功能发生了慢性改变。海马体中 NMDAR 功能的升高可能是低 LG 后代 LTP 受损的基础。
