Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, 7925, South Africa.
Brain Res. 2013 Feb 25;1497:23-31. doi: 10.1016/j.brainres.2012.12.029. Epub 2012 Dec 28.
Experiencing early life stress increases the risk of developing a psychiatric disorder later in life, possibly by altering neural networks, such as the locus-coeruleus norepinephrine (LC-NE) system. Whether early life stress affects the LC-NE system directly, or whether the effects are via changes in glutamate and GABA modulation of the LC-NE system, is unclear. Early life stress has been shown to alter glutamate and GABA transmission, and in particular, to alter GABA(A) receptor expression. The LC-NE system has been implicated in attention-deficit/hyperactivity disorder (ADHD), amongst other disorders, and is over-responsive to glutamate stimulation in a validated rat model of ADHD, the spontaneously hypertensive rat (SHR). It is plausible that the LC-NE system, or glutamate and GABA modulation thereof, in an individual already genetically predisposed to develop ADHD, or in SHR, may respond in a unique way to early life stress. To investigate this we applied a mild developmental stressor, maternal separation, onto SHR, and onto their control strain, Wistar-Kyoto rats (WKY), from post-natal day (P)2-14. On P50-52, in early adulthood, we assayed glutamate and potassium stimulated release of radio-actively labelled NE ((3)[H]NE) from hippocampal slices using an in vitro superfusion technique, in the presence or absence of a GABA(A) receptor antagonist, bicuculline. Our results show that maternal separation altered GABA(A) receptor-mediated modulation of NE release in the hippocampus of the two strains in opposite directions, increasing it in SHR and decreasing it in WKY. Our findings indicate that effects of early life stress are highly dependent on genetic predisposition, since opposite changes in GABA(A) receptor-mediated modulation of NE release were observed in the rat model of ADHD, SHR, and their control strain, WKY.
早期生活压力会增加晚年患精神障碍的风险，这可能是通过改变神经网络实现的，例如蓝斑-去甲肾上腺素（LC-NE）系统。早期生活压力是否直接影响 LC-NE 系统，或者其影响是否通过改变谷氨酸和 GABA 对 LC-NE 系统的调节来实现，目前尚不清楚。早期生活压力已被证明会改变谷氨酸和 GABA 的传递，特别是改变 GABA(A)受体的表达。LC-NE 系统与注意力缺陷多动障碍（ADHD）等疾病有关，并且在 ADHD 的一种经过验证的大鼠模型（自发性高血压大鼠，SHR）中，对谷氨酸刺激的反应过度，即 LC-NE 系统。LC-NE 系统，或者已经遗传易患 ADHD 的个体或 SHR 中的谷氨酸和 GABA 调节，可能会以独特的方式对早期生活压力作出反应，这是合理的。为了研究这一点，我们对 SHR 及其对照品系 Wistar-Kyoto 大鼠（WKY）施加了轻度发育应激源，即母婴分离，从出生后第 2-14 天开始。在成年早期（P50-52 天），我们使用体外超滤液技术，在存在或不存在 GABA(A)受体拮抗剂（bicuculline）的情况下，检测海马切片中放射性标记 NE（[3][H]NE）的谷氨酸和钾刺激释放。我们的结果表明，母婴分离以相反的方式改变了两种品系海马中 GABA(A)受体介导的 NE 释放调节，在 SHR 中增加，在 WKY 中减少。我们的研究结果表明，早期生活压力的影响高度依赖于遗传易感性，因为在 ADHD 的大鼠模型 SHR 及其对照品系 WKY 中，观察到 GABA(A)受体介导的 NE 释放调节的相反变化。
