Entorhinal cortex layer III Adgrl2 expression controls topographical circuit connectivity required for sequence learning.

The entorhinal cortex and hippocampus are interconnected brain regions required for episodic learning and memory. For this functional encoding, correct assembly of specific synaptic connections across this circuit is critical during development. To guide the connection specificity between neurons, a multitude of circuit building molecular components are required, including the latrophilin family of adhesion G protein-coupled receptors (Lphn1-3; gene symbols Adgrl1-3). Within this genetic family, Adgrl2 exhibits a unique topographical and cell-type specific expression patterning in the entorhinal cortex and hippocampus that mirrors connectivity. To investigate the role of Adgrl2 in a cell-type specific fashion for this circuit, we here created a transgenic mouse (Adgrl2^fl/fl;pOxr1-Cre) with targeted and selective Adgrl2 deletion in medial entorhinal cortex layer III neurons (MECIII). Using these mice, we find two major input/output circuitry pathways to be topographically shifted with Adgrl2 deletion in MECIII neurons. These neural connectivity impacts include MECIII axon projections to contralateral MEC layer I, and presubiculum axons to ipsilateral MEC layer III. To test the behavioral consequences of these circuitry alterations, we investigated varying entorhinal cortex dependent behaviors, revealing selective deficits in spatial-temporal sequence learning. Taken together, this study demonstrates that Adgrl2 expression in MECIII neurons is necessary for the accurate assembly of MEC topographical circuits that support episodic learning.