Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia.
Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia.
复制标题
DOI：
10.1016/j.ijdevneu.2011.02.006
复制
发表时间：
2011-05
影响因子：
1.8
通讯作者：
Arnsten, Amy F. T.
中科院分区：
文献类型：
--
作者：
Arnsten, Amy F. T.
精神分裂症的症状涉及前额皮质（PFC）的严重功能障碍。 PFC 网络创建了我们的“心理素描本”，PFC 功能障碍会导致认知缺陷、思维障碍、妄想和幻觉等症状。精神分裂症的神经病理学研究表明，深层 III（PFC 微电路所在的亚层）中的树突棘明显丧失。微电路由循环兴奋性锥体细胞网络组成，这些网络在脊柱上互连，并通过 NMDA 受体信号传导相互兴奋。锥体细胞的持续放电是由 GABA 能篮状细胞和吊灯细胞的侧向抑制塑造的，从而产生准确的表征知识（即工作记忆）所需的调整的持续放电。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着而灵活地改变，这一过程称为动态网络连接（DNC）。 DNC 蛋白（例如 HCN 通道）集中在深层 III 的树突棘上。在最佳条件下，锥体细胞的网络输入通过去甲肾上腺素能 α-2A 对 cAMP-HCN 通道信号传导的抑制得到加强，并通过多巴胺 D1-cAMP-HCN 通道减弱不适当的输入来塑造。然而，当受到压力时，高水平的 cAMP-HCN 通道信号传导会导致网络放电崩溃。随着慢性压力暴露，脊柱尺寸减小并消失，这个过程涉及 PKC 信号传导的增加。重要的是，通常加强 PFC 网络连接和/或逆转应激反应的分子在精神分裂症中通常会发生基因改变。由于暴露于压力是导致精神分裂症症状的关键因素，因此深层 III 中这些失调的信号通路可能与已经脆弱的电路相互作用，导致脊柱损失和陷入疾病。
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.
登录
查看更多内容
影响因子：
4.5
作者：
Eack, Shaun M.;George, Manish M.;Prasad, Konasale M. R.;Keshavan, Matcheri S.
通讯作者：
Keshavan, Matcheri S.
影响因子：
3.3
作者：
Duffy, A. M.;Zhou, P.;Milner, T. A.;Pickel, V. M.
通讯作者：
Pickel, V. M.
影响因子：
56.9
作者：
Buschman, Timothy J.;Miller, Earl K.
通讯作者：
Miller, Earl K.
影响因子：
--
作者：
Cannon, TD;Hennah, W;Peltonen, L
通讯作者：
Peltonen, L
影响因子：
56.9
作者：
Birnbaum, SG;Yuan, PX;Arnsten, AFT
通讯作者：
Arnsten, AFT