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Neurexophilins are secreted neuropeptide-like glycoproteins, and neurexophilin1 and neurexophilin3 are ligands for the presynaptic cell adhesion molecule α-neurexin. Neurexophilins are more selectively expressed in the brain than α-neurexins, however, which led us to ask whether neurexophilins modulate the function of α-neurexin in a context-specific manner. We characterized the expression and function of neurexophilin4 in mice and found it to be expressed in subsets of neurons responsible for feeding, emotion, balance, and movement. Deletion of  Neurexophilin4  caused corresponding impairments, most notably in motor learning and coordination. We demonstrated that neurexophilin4 interacts with α-neurexin and GABA A Rs in the cerebellum. Loss of  Neurexophilin4  impaired cerebellar Golgi-granule inhibitory neurotransmission and synapse number, providing a partial explanation for the motor learning and coordination deficits observed in the  Neurexophilin4  null mice. Our data illustrate how selectively expressed Neurexophilin4, an α-neurexin ligand, regulates specific synapse function and modulates cerebellar motor control.

Neurexophilin4 is a selectively expressed α-neurexin ligand that modulates specific cerebellar synapses and motor functions