Neurexin-3 defines synapse- and sex-dependent diversity of GABAergic inhibition in ventral subiculum

Abstract

Ventral subiculum (vSUB) is integral to the regulation of stress and reward, however the intrinsic connectivity and synaptic properties of the inhibitory local circuit are poorly understood. Neurexin-3 (Nrxn3) is highly expressed in hippocampal inhibitory neurons, but its function at inhibitory synapses has remained elusive. Using slice electrophysiology, imaging, and single-cell RNA sequencing, we identify multiple roles for Nrxn3 at GABAergic parvalbumin (PV) interneuron synapses made onto vSUB regular spiking (RS) and burst spiking (BS) principal neurons. Surprisingly, we found that intrinsic connectivity and synaptic function of Nrxn3 in vSUB are sexually dimorphic. We reveal that vSUB PVs make preferential contact with RS neurons in males, but BS neurons in females. Furthermore, we determined that despite comparable Nrxn3 isoform expression in male and female PV neurons, Nrxn3 maintains synapse density at PV-RS synapses in males, but suppresses presynaptic release at the same synapses in females. HighlightsO_LIOverall inhibitory strength in ventral subiculum is cell-type specific C_LIO_LIPV circuits in ventral subiculum are organized sex-specifically C_LIO_LINrxn3 function in PV interneurons depends on postsynaptic cell identity C_LIO_LINrxn3 has distinct functions at PV-RS synapses in females compared to males C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/440943v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@7fcf99org.highwire.dtl.DTLVardef@1167f82org.highwire.dtl.DTLVardef@d5c79org.highwire.dtl.DTLVardef@1320f09_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG