Arnsten Amy F T
Department of Neurobiology, Yale Medical School, 333 Cedar St., New Haven, CT 06510, USA.
Int J Dev Neurosci. 2011 May;29(3):215-23. doi: 10.1016/j.ijdevneu.2011.02.006. Epub 2011 Feb 21.
The symptoms of schizophrenia involve profound dysfunction of the prefrontal cortex (PFC). PFC networks create our "mental sketch pad", and PFC dysfunction contributes to symptoms such as cognitive deficits, thought disorder, delusions and hallucinations. Neuropathological studies of schizophrenia have shown marked loss of dendritic spines in deep layer III, the sublayer where PFC microcircuits reside. The microcircuits consist of recurrent excitatory pyramidal cell networks that interconnect on spines, and excite each other via NMDA receptor signaling. The pyramidal cell persistent firing is sculpted by lateral inhibition from GABAergic basket and chandelier cells, thus creating tuned, persistent firing needed for accurate representational knowledge (i.e., working memory). The strength of pyramidal cell network connections is markedly and flexibly altered by intracellular signaling pathways in dendritic spines, a process called dynamic network connectivity (DNC). DNC proteins such as HCN channels are concentrated on dendritic spines in deep layer III. Under optimal conditions, network inputs to pyramidal cells are strengthened by noradrenergic alpha-2A inhibition of cAMP-HCN channel signaling, and sculpted by dopamine D1-cAMP-HCN channel weakening of inappropriate inputs. However, with stress exposure, high levels of cAMP-HCN channel signaling produces a collapse in network firing. With chronic stress exposure, spines reduce in size and are lost, and this process involves increased PKC signaling. Importantly, molecules that normally strengthen PFC networks connections and/or reverse the stress response, are often genetically altered in schizophrenia. As exposure to stress is a key factor in the precipitation of schizophrenic symptoms, these dysregulated signaling pathways in deep layer III may interact with already vulnerable circuitry to cause spine loss and the descent into illness.
精神分裂症的症状涉及前额叶皮质（PFC）的严重功能障碍。PFC网络创建我们的“心理速写本”，而PFC功能障碍会导致认知缺陷、思维紊乱、妄想和幻觉等症状。对精神分裂症的神经病理学研究表明，位于PFC微电路所在的深层III中，树突棘显著丢失。这些微电路由在树突棘上相互连接并通过NMDA受体信号相互激发的反复兴奋性锥体细胞网络组成。锥体细胞的持续放电由来自GABA能篮状细胞和吊灯细胞的侧向抑制塑造，从而产生准确表征知识（即工作记忆）所需的调谐、持续放电。锥体细胞网络连接的强度通过树突棘中的细胞内信号通路显著且灵活地改变，这一过程称为动态网络连接性（DNC）。诸如HCN通道等DNC蛋白集中在深层III的树突棘上。在最佳条件下，去甲肾上腺素能α-2A对cAMP-HCN通道信号的抑制会增强锥体细胞的网络输入，并通过多巴胺D1-cAMP-HCN通道对不适当输入的减弱来塑造。然而，在应激暴露时，高水平的cAMP-HCN通道信号会导致网络放电崩溃。长期应激暴露会使树突棘尺寸减小并丢失，这一过程涉及PKC信号增加。重要的是，通常增强PFC网络连接和/或逆转应激反应的分子在精神分裂症中常常发生基因改变。由于应激暴露是精神分裂症症状发作的关键因素，深层III中这些失调的信号通路可能与已经脆弱的神经回路相互作用，导致树突棘丢失并陷入疾病状态。
