Entorhinal cortex glutamatergic and GABAergic projections bidirectionally control discrimination and generalization...

Discrimination and generalization are crucial brain-wide functions for memory and object recognition that utilize pattern separation and completion computations. Circuit mechanisms supporting these operations remain enigmatic. We show lateral entorhinal cortex glutamatergic (LEC _GLU ) and GABAergic (LEC _GABA ) projections are essential for object recognition memory. Silencing LEC _GLU during in vivo two-photon imaging increased the population of active CA3 pyramidal cells but decreased activity rates, suggesting a sparse coding function through local inhibition. Silencing LEC _GLU also decreased place cell remapping between different environments validating this circuit drives pattern separation and context discrimination. Optogenetic circuit mapping confirmed that LEC _GLU drives dominant feedforward inhibition to prevent CA3 somatic and dendritic spikes. However, conjunctively active LEC _GABA suppresses this local inhibition to disinhibit CA3 pyramidal neuron soma and selectively boost integrative output of LEC and CA3 recurrent network. LEC _GABA thus promotes pattern completion and context generalization. Indeed, without this disinhibitory input, CA3 place maps show decreased similarity between contexts. Our findings provide circuit mechanisms whereby long-range glutamatergic and GABAergic cortico-hippocampal inputs bidirectionally modulate pattern separation and completion, providing neuronal representations with a dynamic range for context discrimination and generalization.