条件性神经黏附蛋白-2 敲除成年内侧前额叶皮质导致突触抑制的慢性变化与认知障碍有关。
Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments.
机构信息
1] Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA [2] Department of Neurosurgery, Stanford University, Stanford, CA, USA [3] Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA [4] Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
出版信息
Mol Psychiatry. 2015 Jul;20(7):850-9. doi: 10.1038/mp.2015.31. Epub 2015 Mar 31.
Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs.
内侧前额叶皮层（mPFC）的异常活动在神经精神疾病中经常被观察到，但涉及的机制仍不清楚。慢性异常兴奋和/或抑制 mPFC 神经元被认为会导致认知障碍。然而，由于技术上难以以慢性、局部限制但又特定的方式控制突触特性，因此缺乏对此假设的直接证据。在这里，我们生成了神经黏附分子-2（Nlgn2）的条件敲除（cKO）小鼠，该分子是与神经精神疾病相关的抑制性突触的突触后细胞黏附分子。成年 mPFC 中的 Nlgn2 cKO 在 2-3 周后使 Nlgn2 蛋白无法检测到，但仅在 6-7 周后就导致了突触抑制的显著减少，并导致焦虑、恐惧记忆和社会互动行为的平行损伤。此外，Nlgn2 的 cKO 严重损害了 mPFC 中即时早期基因表达的行为刺激，这表明慢性抑制性突触减少使 mPFC 与经验依赖性输入脱耦。我们的研究结果表明，Nlgn2 是成年 mPFC 中抑制性突触持续维持所必需的，而局部抑制的慢性损害通过部分使 mPFC 与经验诱导的输入脱耦，从而使 mPFC 脱离其认知功能。
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