Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI) Wako, Saitama 351-0198, Japan.
Department of Integrative Physiology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Nat Commun. 2017 Jun 12;8:15800. doi: 10.1038/ncomms15800.
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 是一种 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，其在高级大脑功能中的作用及其潜在机制尚不清楚。在这里，我们发现 Lrfn2 敲除小鼠表现出自闭症样行为异常，包括社交回避、发声减少、刻板行为增加和条件反射抑制缺陷，同时伴有学习和记忆能力增强。在海马体中，突触后密度 95（PSD-95）和谷氨酸受体 1（GluA1）的水平降低。突触结构和功能不成熟，表现为梭形棘突、较小的突触后密度、AMPA/NMDA 比值降低和长时程增强（LTP）增强。体外实验表明，AMPA 受体的突触表面表达依赖于 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组成部分，其功能障碍导致病理性不成熟/沉默突触。
