Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, United States; Brudnick Neuropsychiatric Research Institute, University of Massachusetts, Worcester, United States; Medical Scientist Training Program, University of Massachusetts, Worcester, United States
Kotaro Konno
Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Japan
Yuka Imamura
Departments of Pharmacology and Biochemistry & Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, United States
Aya Matsui
Vollum Institute, Oregon Health & Science University, Portland, United States
Manabu Abe
Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan
Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University, Niigata, Japan
Takeshi Uemura
Division of Gene Research, Research Center for Advanced Science, Shinshu University, Nagano, Japan; Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano, Japan
Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, United States; Brudnick Neuropsychiatric Research Institute, University of Massachusetts, Worcester, United States
Extensive serotonin (5-hydroxytryptamine, 5-HT) innervation throughout the brain corroborates 5-HT’s modulatory role in numerous cognitive activities. Volume transmission is the major mode for 5-HT transmission but mechanisms underlying 5-HT signaling are still largely unknown. Abnormal brain 5-HT levels and function have been implicated in autism spectrum disorder (ASD). Neurexin (Nrxn) genes encode presynaptic cell adhesion molecules important for the regulation of synaptic neurotransmitter release, notably glutamatergic and GABAergic transmission. Mutations in Nrxn genes are associated with neurodevelopmental disorders including ASD. However, the role of Nrxn genes in the 5-HT system is poorly understood. Here, we generated a mouse model with all three Nrxn genes disrupted specifically in 5-HT neurons to study how Nrxns affect 5-HT transmission. Loss of Nrxns in 5-HT neurons reduced the number of serotonin neurons in the early postnatal stage, impaired 5-HT release, and decreased 5-HT release sites and serotonin transporter expression. Furthermore, 5-HT neuron-specific Nrxn knockout reduced sociability and increased depressive-like behavior. Our results highlight functional roles for Nrxns in 5-HT neurotransmission, 5-HT neuron survival, and the execution of complex behaviors.
