The Role of Neurexins in Serotonin Signaling and Complex Behaviors

Abstract

Extensive serotonin (5-HT) fiber innervation throughout the brain corroborates 5-HT’s modulatory role in numerous behaviors including social behavior, emotion regulation, and learning and memory. Abnormal brain 5-HT levels and function are implicated in Autism Spectrum Disorder (ASD) which often co-occurs with other neuropsychiatric conditions. While 5-HT therapeutics are used to treat ASD, variable improvements in symptomatology require further investigation of 5-HT-mediated pathology. Neurexins (Nrxns) are presynaptic cell adhesion molecules that maintain synapse function for proper neural circuit assembly. Given that aberrant Nrxn and 5-HT function independently contribute to signaling pathology and behavioral impairments, it is critical to understand how Nrxn-mediated 5-HT neurotransmission participates in pathological mechanisms underlying ASD. Using fluorescence in situ hybridization, I found that the three Nrxn genes (Nrxn1, Nrxn2, and Nrxn3) are differentially expressed in 5-HT neurons in the dorsal raphe nucleus (DRN) and median raphe nucleus which contain the primary source of 5-HT neurons in the brain. Our lab generated a mouse model with selective deletion of Nrxns in 5-HT neurons to investigate the function of Nrxns in 5-HT signaling. The loss of Nrxns at 5-HT release sites reduced 5-HT release in the DRN and hippocampus and altered 5-HT innervation in specific brain regions. The lack of 5-HTergic Nrxns also reduced sociability and increased depressive-like behavior in males. This mouse model provides mechanisms to shed new light on 5-HT neurotransmission in the generation of complex behaviors.