Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, NSW 2006, Australia; Schizophrenia Research Institute, Garvan Institute, Victoria Rd, Darlinghurst, Australia.
Pharmacol Res. 2018 Feb;128:179-189. doi: 10.1016/j.phrs.2017.09.021. Epub 2017 Sep 29.
Variations in the early postnatal environment of rodents produce long-term changes in responses to stress that may underlie neuropsychiatric diseases such as anxiety, depression and schizophrenia. GABA receptors undergo marked changes in their subunit composition during this period, involving a regionally-dependent replacement of α with α subunits, the so-called α-subunit switch. In this study we examined the effects of early-life environment on adulthood GABA receptor α and α subunit expression and the synaptic clustering of GABA receptors. Male and female mice were exposed to either 15min daily handling sessions (EH) or no intervention (NH) over postnatal day (PND) 1-14. Adulthood behavioural differences in anxiety were assessed on the elevated plus-maze. Immunoperoxidase histochemistry was used to examine the density of the α and α subunit proteins. Double-labelling immunofluorescence and confocal microscopy were used to study GABA receptor synaptic clustering. NH animals showed increased anxiety-type behaviours in the elevated plus maze relative to EH mice. NH males showed a loss of α subunits from the thalamus and lower layers of the somatosensory cortex, whilst NH females showed a reduction of α but increase in α protein in lower layers of the primary somatosensory cortex only. The NH condition also reduced α subunit expression in dentate gyrus (DG) in both males and females. Regardless of sex, NH mice showed reduced colocalisation of GABA receptor α subunits with the synaptic marker gephyrin relative to the control condition. These findings suggest that early-life environment has long-lasting effects on GABA receptors, leading to long-term changes in adulthood behaviour, and are of relevance to neurodevelopmental explanations of stress-augmented neuropsychiatric disorders.
啮齿动物产后早期环境的变化会导致对压力的反应产生长期变化，而这种变化可能是焦虑、抑郁和精神分裂症等神经精神疾病的基础。在这段时间内，GABA 受体的亚基组成发生了显著变化，涉及到 α 亚基的区域性替代，即所谓的 α 亚基转换。在这项研究中，我们研究了早期生活环境对成年 GABA 受体 α 和 α 亚基表达以及 GABA 受体突触聚集的影响。雄性和雌性小鼠在出生后第 1 天到第 14 天期间每天接受 15 分钟的处理（EH）或不干预（NH）。成年焦虑的行为差异在高架十字迷宫上进行评估。免疫过氧化物酶组织化学用于检查 α 和 α 亚基蛋白的密度。双标记免疫荧光和共聚焦显微镜用于研究 GABA 受体的突触聚集。NH 动物在高架十字迷宫中表现出焦虑样行为增加，相对 EH 小鼠。NH 雄性动物的丘脑和躯体感觉皮层的较低层中失去了 α 亚基，而 NH 雌性动物仅在初级躯体感觉皮层的较低层中减少了 α 亚基但增加了 α 蛋白。NH 条件还降低了雄性和雌性动物齿状回（DG）中 α 亚基的表达。无论性别如何，NH 小鼠的 GABA 受体 α 亚基与突触标记物 gephyrin 的共定位均低于对照条件。这些发现表明，早期生活环境对 GABA 受体具有持久的影响，导致成年后行为发生长期变化，这与应激增强神经精神疾病的神经发育解释有关。
