Neurexins in serotonergic neurons regulate neuronal survival, serotonin transmission, and complex mouse behaviors

Abstract

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 (<i>Nrxn</i>) genes encode presynaptic cell adhesion molecules important for the regulation of synaptic neurotransmitter release, notably glutamatergic and GABAergic transmission. Mutations in <i>Nrxn</i> genes are associated with neurodevelopmental disorders including ASD. However, the role of <i>Nrxn</i> genes in the 5-HT system is poorly understood. Here, we generated a mouse model with all three <i>Nrxn</i> genes disrupted specifically in 5-HT neurons to study how Nrxns affect 5-HT transmission. Loss of <i>Nrxns</i> 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 <i>Nrxn</i> 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.