Presynaptic Nrxn3 is essential for ribbon-synapse maturation in hair cells.

ABSTRACT

Hair cells of the inner ear and lateral-line system rely on specialized ribbon synapses to transmit sensory information to the central nervous system. The molecules required to assemble these synapses are not fully understood. We show that Nrxn3, a presynaptic adhesion molecule, is critical for ribbon-synapse maturation in hair cells. In both mouse and zebrafish models, the loss of Nrxn3 results in significantly fewer intact ribbon synapses. We show in zebrafish that initially, nrxn3 mutants have normal pre- and post-synapse numbers, but synapses fail to pair, leading to postsynapse loss. We also demonstrate that Nrxn3 subtly influences synapse selectivity in zebrafish lateral-line hair cells that detect anterior flow. A 60% loss of synapses in zebrafish nrxn3 mutants dramatically reduces pre- and post-synaptic responses. Despite fewer synapses, auditory responses in zebrafish and mice are unaffected. This work demonstrates that Nrxn3 is a critical and conserved molecule required for the maturation of ribbon synapses. Understanding how ribbon synapses mature is essential to generating novel therapies to treat synaptopathies linked to auditory or vestibular dysfunction.