Feller_2026_eNeuro__

Neurexins (Nrxns) are presynaptic cell adhesion molecules essential for synapse development and function. Of the many neurexin isoforms, only beta-Nrxns contain the histidine-rich domain (HRD). While the HRD has been implicated in several pathological contexts, its normal physiological role remains unclear. To address this, we used a CRISPR-Cas9 method to generate a new mouse line expressing in-frame truncated Nrxn1beta lacking the HRD. We found that HRD deletion did not affect mouse viability, gross brain development, or general behavior of either sex. However, loss of the HRD significantly altered neuroligin-1-dependent excitatory, but not inhibitory, presynaptic differentiation in primary cultured neurons. Moreover, this deletion affected presynaptic short-term plasticity, but not basal synaptic transmission, at hippocampal Schaffer collateral-CA1 synapses. These findings identify the Nrxn1beta HRD as a potential contributor to excitatory presynaptic organization and function, providing new insight into the molecular diversity and specialization of Nrxns.Significance statement The histidine-rich domain (HRD) is a unique domain of beta-Nrxns, absent from alpha-Nrxns, that mediates the binding of pathological proteins. This study investigates the physiological functions of the Nrxn1beta HRD by generating and characterizing a new mouse line expressing a truncated Nrxn1beta mutant lacking its HRD. We found that Nrxn1beta HRD deletion affects paired pulse facilitation, a form of short-term presynaptic plasticity, and neuroligin-1-mediated excitatory presynaptic organization without affecting overall brain development, synapse formation, basal synaptic transmission, or mouse behavior. These findings highlight the critical role of Nrxn1beta HRD in excitatory presynaptic organization and function. This work will open new avenues for studying isoform-specific mechanisms of Nrxns for synaptic regulation and their potential implications in both physiological and pathological contexts.