Entorhinal cortex layer III ADGRL2 expression controls topographical circuit connectivity required for sequence learning

Abstract

Abstract 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 a critical component during development. To guide the connection specificity that exists between neurons requires a multitude of circuit building molecular components, including the latrophilin family of synaptic cell adhesion molecules (Lphn1-3; gene symbols ADGRL1-3). Of this genetic family, Lphn2 (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 Lphn2 in a specific cell-type in this circuit, we here created a transgenic mouse (Lphn2fl/fl;pOXR1-Cre) with targeted Lphn2 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 Lphn2 deletion in MECIII neurons that 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 recognition. Taken together, this study demonstrates that Lphn2 expression in MECIII neurons is necessary for the accurate assembly of MEC topographical circuits that support episodic learning.