Bennett A O Maxwell R
Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia.
Aust N Z J Psychiatry. 2008 Dec;42(12):995-1002. doi: 10.1080/00048670802512073.
Stress during childhood and adolescence has implications for the extent of depression and psychotic disorders in maturity. Stressful events lead to the regression of synapses with the loss of synaptic spines and in some cases whole dendrites of pyramidal neurons in the prefrontal cortex, a process that leads to the malfunctioning of neural networks in the neocortex. Such stress often shows concomitant increases in the activity of the hypothalamic-pituitary-adrenal system, with a consequent elevated release of glucocorticoids such as cortisol as well as of corticotropin-releasing hormone (CRH) from neurons. It is very likely that it is these hormones, acting on neuronal and astrocyte glucocorticoid receptors (GRs) and CRH receptors, respectively, that are responsible for the regression of synapses. The mechanism of such regression involves the loss of synaptic spines, the stability of which is under the direct control of the activity of N-methyl-d-aspartate (NMDA) receptors on the spines. Glutamate activates NMDA receptors, which then, through parallel pathways, control the extent in the spine of the cytoskeletal protein F-actin and so spine stability and growth. Both GR and CRH receptors in the spines can modulate NMDA receptors, reducing their activation by glutamate and hence spine stability. In contrast, glucocorticoids, probably acting on nerve terminal and astrocyte GRs, can release glutamate, so promoting NMDA receptor activation. It is suggested that spine stability is under dual control by glucocorticoids and CRH, released during stress to change the stability of synaptic spines, leading to the malfunctioning of cortical neural networks that are involved in depression and psychoses.
童年和青少年时期的压力会对成年后的抑郁程度和精神障碍产生影响。压力事件会导致突触退化，伴有突触棘的丧失，在某些情况下还会导致前额叶皮质锥体细胞的整个树突退化，这一过程会导致新皮质神经网络功能失调。这种压力通常伴随着下丘脑 - 垂体 - 肾上腺系统活动的增加，从而导致皮质醇等糖皮质激素以及神经元释放促肾上腺皮质激素释放激素（CRH）的水平升高。很可能正是这些分别作用于神经元和星形胶质细胞糖皮质激素受体（GRs）以及CRH受体的激素，导致了突触的退化。这种退化机制涉及突触棘的丧失，其稳定性直接受棘上N - 甲基 - D - 天冬氨酸（NMDA）受体活性的控制。谷氨酸激活NMDA受体，然后通过平行途径控制棘内细胞骨架蛋白F - 肌动蛋白的程度，进而控制棘的稳定性和生长。棘中的GR和CRH受体都可以调节NMDA受体，减少谷氨酸对它们的激活，从而降低棘的稳定性。相反，糖皮质激素可能作用于神经末梢和星形胶质细胞的GRs，释放谷氨酸，从而促进NMDA受体的激活。有人认为，突触棘的稳定性受糖皮质激素和CRH的双重控制，在压力期间释放，以改变突触棘的稳定性，导致参与抑郁和精神病的皮质神经网络功能失调。
