Department of Medical Pharmacology, Nagasaki University Institute of Biomedical Sciences, Nagasaki, 852-8523, Japan.
Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, 351-0198, Japan.
Commun Biol. 2022 Sep 9;5(1):935. doi: 10.1038/s42003-022-03891-y.
SLITRK1 is an obsessive-compulsive disorder spectrum-disorders-associated gene that encodes a neuronal transmembrane protein. Here we show that SLITRK1 suppresses noradrenergic projections in the neonatal prefrontal cortex, and SLITRK1 functions are impaired by SLITRK1 mutations in patients with schizophrenia (S330A, a revertant of Homo sapiens-specific residue) and bipolar disorder (A444S). Slitrk1-KO newborns exhibit abnormal vocalizations, and their prefrontal cortices show excessive noradrenergic neurites and reduced Semaphorin3A expression, which suppresses noradrenergic neurite outgrowth in vitro. Slitrk1 can bind Dynamin1 and L1 family proteins (Neurofascin and L1CAM), as well as suppress Semaphorin3A-induced endocytosis. Neurofascin-binding kinetics is altered in S330A and A444S mutations. Consistent with the increased obsessive-compulsive disorder prevalence in males in childhood, the prefrontal cortex of male Slitrk1-KO newborns show increased noradrenaline levels, and serotonergic varicosity size. This study further elucidates the role of noradrenaline in controlling the development of the obsessive-compulsive disorder-related neural circuit.
SLITRK1 是一种强迫症谱系障碍相关基因，编码一种神经元跨膜蛋白。我们在此表明，SLITRK1 抑制了新生儿前额皮质中的去甲肾上腺素能投射，并且精神分裂症（S330A，人类特异性残基的回复突变）和双相情感障碍（A444S）患者的 SLITRK1 突变会损害 SLITRK1 的功能。Slitrk1-KO 新生儿表现出异常发声，其前额皮质显示出过多的去甲肾上腺素能神经突和减少的 Semaphorin3A 表达，这在体外抑制去甲肾上腺素能神经突的生长。Slitrk1 可以结合 Dynamin1 和 L1 家族蛋白（Neurofascin 和 L1CAM），并抑制 Semaphorin3A 诱导的内吞作用。S330A 和 A444S 突变改变了神经纤丝结合动力学。与儿童时期男性强迫症患病率增加一致，雄性 Slitrk1-KO 新生儿的前额皮质显示去甲肾上腺素水平升高，5-羟色胺能末梢增大。本研究进一步阐明了去甲肾上腺素在控制强迫症相关神经回路发育中的作用。
