Parahippocampal latrophilin-2 (ADGRL2) expression controls topographical presubiculum to entorhinal cortex circuit connectivity.

Brain circuits are comprised of distinct interconnected neurons that are assembled by synaptic recognition molecules presented by defined pre- and post-synaptic neurons. This cell-cell recognition process is mediated by varying cellular adhesion molecules, including the latrophilin family of adhesion G-protein-coupled receptors. Focusing on parahippocampal circuitry, we find that latrophilin-2 (Lphn2; gene symbol ADGRL2) is specifically enriched in interconnected subregions of the medial entorhinal cortex (MEC), presubiculum (PrS), and parasubiculum (PaS). Retrograde viral tracing from the Lphn2-enriched region of the MEC reveals unique topographical patterning of inputs arising from the PrS and PaS that mirrors Lphn2 expression. Using a Lphn2 conditional knockout mouse model, we find that deletion of MEC Lphn2 expression selectively impairs retrograde viral labeling of inputs arising from the ipsilateral PrS. Combined with analysis of Lphn2 expression within the MEC, this study reveals Lphn2 to be selectively expressed by defined cell types and essential for MEC-PrS circuit connectivity.