Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses

α- and β-neurexins are presynaptic cell-adhesion molecules whose general importance for synaptic transmission is well documented. The specific functions of neurexins, however, remain largely unknown because no conditional neurexin knockouts are available, and because targeting all α- and β-neurexins produced by a particular gene is challenging. Using newly-generated constitutive and conditional knockout mice that target all neurexin-3α and -3β isoforms, we here show that neurexin-3 is differentially required for distinct synaptic functions in different brain regions. Specifically, we find that in cultured neurons and acute slices of the hippocampus, presynaptic neurexin-3 mediates trans-synaptic regulation of postsynaptic AMPA-receptors via its extracellular sequences. In cultured neurons and acute slices of the olfactory bulb, however, presynaptic neurexin-3 is selectively required for GABA release by a mechanism involving its intracellular sequences. Thus, our data demonstrate that neurexin-3 performs distinct essential pre- or postsynaptic functions in different brain regions by distinct mechanisms.