Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice.
Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice.
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DOI：
10.1038/ncomms15800
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发表时间：
2017-06-12
影响因子：
16.6
通讯作者：
Aruga J
中科院分区：
文献类型：
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作者：
Morimura N;Yasuda H;Yamaguchi K;Katayama KI;Hatayama M;Tomioka NH;Odagawa M;Kamiya A;Iwayama Y;Maekawa M;Nakamura K;Matsuzaki H;Tsujii M;Yamada K;Yoshikawa T;Aruga J
Lrfn2/SALM1是一种与PSD-95相互作用的突触黏附分子，人类LRFN2与学习障碍有关。然而，它在高级大脑功能中的作用和潜在的机制仍不清楚。在这里，我们发现Lrfn2基因敲除小鼠表现出自闭症样行为异常，包括社交退缩、发声交流减少、刻板印象活动增加和脉搏前抑制缺陷，以及学习和记忆增强。在海马区，突触PSD-95和GluA1的水平降低。这些突触在结构和功能上都不成熟，具有纺锤形的棘突，突触后密度较小，AMPA/NMDA比率降低，LTP增强。体外实验表明，AMPAR突触表面的表达依赖于Lrfn2和PSD-95之间的直接相互作用。此外，我们在自闭症和精神分裂症患者中检测到功能缺陷的LRFN2错义突变。综上所述，这些发现表明Lrfn2/LRFn2是兴奋性突触成熟和维持的核心成分，它们的功能障碍导致了具有病理生理状态的未成熟/沉默突触。Lrfn2/SALM1是一种突触黏附分子，已知与PSD-95相互作用。在这里，作者表明Lrfn2调节兴奋性突触的成熟和维持，Lrfn2基因敲除的小鼠表现出自闭症样行为以及增强的学习和记忆。
Lrfn2/SALM1 is a PSD-95-interacting synapse adhesion molecule, and human LRFN2 is associated with learning disabilities. However its role in higher brain function and underlying mechanisms remain unknown. Here, we show that Lrfn2 knockout mice exhibit autism-like behavioural abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits, together with enhanced learning and memory. In the hippocampus, the levels of synaptic PSD-95 and GluA1 are decreased. The synapses are structurally and functionally immature with spindle shaped spines, smaller postsynaptic densities, reduced AMPA/NMDA ratio, and enhanced LTP. In vitro experiments reveal that synaptic surface expression of AMPAR depends on the direct interaction between Lrfn2 and PSD-95. Furthermore, we detect functionally defective LRFN2 missense mutations in autism and schizophrenia patients. Together, these findings indicate that Lrfn2/LRFN2 serve as core components of excitatory synapse maturation and maintenance, and their dysfunction causes immature/silent synapses with pathophysiological state. Lrfn2/SALM1 is a synaptic adhesion molecule, and is known to interact with PSD-95. Here the authors show that Lrfn2 regulates excitatory synapse maturation and maintenance, and that Lrfn2 knockout mice exhibit autism-like behaviours as well as enhanced learning and memory.