Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Curr Opin Neurobiol. 2011 Dec;21(6):827-33. doi: 10.1016/j.conb.2011.06.006. Epub 2011 Jul 4.
Recent findings in the genetics of neurodevelopmental syndromes have ushered in an exciting era of discovery in which substrates of neurologic dysfunction are being identified at the synaptic and microcircuit levels in mouse models of these disorders. We review recent progress in this area, focusing on two examples of mouse models of autism spectrum disorders (ASDs): Mecp2 models of Rett syndrome, and a Met-knockout model of non-syndromic forms of autism. In both cases, a dominant theme is changes in synaptic strength, associated with hyper-connectivity or hypo-connectivity in specific microcircuits. Alterations in intrinsic neuronal excitability are also found, but do not appear to be as common. The microcircuit-specific nature of synaptic changes observed in these ASD models indicates that it will be necessary to define mechanisms of circuit dysfunction on a case-by-case basis, not only in neocortex but also in brainstem and other sub-cortical areas. Thus, functional microcircuit analysis is emerging as an important line of investigation, highly complementary to neurogenetic and molecular strategies, and holds promise for generating models of the underlying pathophysiology and for guiding development of novel therapeutic strategies.
神经发育障碍综合征的遗传学研究新发现开创了一个令人兴奋的探索时代，在这些疾病的小鼠模型中，神经系统功能障碍的底物正在突触和微电路水平被识别。我们回顾了这一领域的最新进展，重点关注自闭症谱系障碍（ASD）的两种小鼠模型：Rett 综合征的 Mecp2 模型和非综合征形式自闭症的 Met 敲除模型。在这两种情况下，一个主要的主题是突触强度的变化，与特定微电路中的超连接或低连接相关。还发现了神经元内在兴奋性的改变，但似乎并不常见。在这些 ASD 模型中观察到的微电路特异性突触变化表明，有必要根据具体情况定义电路功能障碍的机制，不仅在新皮层，而且在脑干和其他皮质下区域。因此，功能微电路分析正在成为一种重要的研究方法，它与神经遗传学和分子策略高度互补，并有望生成潜在病理生理学模型，并指导新的治疗策略的发展。
