Latrophilin-1 (Lphn1, a.k.a. CIRL1 and CL1; gene symbol Adgrl1) is an Adhesion GPCR that has been implicated in excitatory synaptic transmission as a candidate receptor for α-latrotoxin. Here we analyzed conditional knockin/knockout mice for Lphn1 that contain an extracellular myc-epitope tag. Mice of both sexes were used in all experiments. Surprisingly, we found that Lphn1 is localized in cultured neurons to synaptic nanoclusters that are present in both excitatory and inhibitory synapses. Conditional deletion of Lphn1 in cultured neurons failed to elicit a detectable impairment in excitatory synapses but produced a decrease in inhibitory synapse numbers and synaptic transmission that was most pronounced for synapses close to the neuronal soma. No changes in axonal or dendritic outgrowth or branching were observed. Our data indicate that Lphn1 is among the few postsynaptic adhesion molecules that are present in both excitatory and inhibitory synapses and that Lphn1 by itself is not essential for excitatory synaptic transmission but contributes to inhibitory synaptic connections.Significance Statement Previously, the Adhesion-GPCRs Latrophilin-2/Latrophilin-3 have been shown to mediate excitatory, but not inhibitory, synapse assembly onto discreet dendritic compartments of hippocampal pyramidal neurons. Here we now show that Latrophilin-1 is targeted to both excitatory and inhibitory hippocampal synapses. Unexpectedly, we find that Latrophilin-1 is selectively essential for directing inhibitory synaptic connections to the neuronal soma. Our work supports a model by which Latrophilins are widely used as organizers of synaptic connectivity that act on a subcellular level. In the light of recent findings connecting haploinsufficiency of Latrophilin-1 to a plethora of neurodevelopmental and neuropsychiatric disorders, our study contributes to our understanding of the molecular mechanisms of Latrophilins that need to be targeted in order to address various pathologies.
Copyright © 2024 Matúš et al.