Robert, V.; O'Neil, K.; Rashid, S. K.; Johnson, C. D.; De La Torre, R. G.; Zemelman, B. V.; Clopath, C.; Basu, J.

Discrimination and generalization, crucial brain-wide functions for memory and object recognition, utilize pattern separation and completion computations. Circuit mechanisms supporting these operations remain enigmatic. We show lateral entorhinal cortex glutamatergic (LECGLU) and GABAergic (LECGABA) projections are essential for object recognition memory. Silencing LECGLU during in vivo imaging suggests a sparse coding function by driving local inhibition to prevent somatic and dendritic spikes, confirmed by optogenetic circuit mapping. Silencing LECGLU decreased place cell remapping between different environments, validating this circuit drives pattern separation. LECGABA suppresses local inhibition to disinhibit CA3 pyramidal neuron soma and selectively boost integrative output of LEC and CA3 recurrent network. LECGABA thus promotes pattern completion. Indeed, without this disinhibitory input, CA3 place maps show decreased similarity between contexts. Our findings provide circuit mechanisms whereby long-range glutamatergic and GABAergic inputs bidirectionally modulate pattern separation and completion, providing hippocampal representations with a dynamic range for context discrimination and generalization.