Cholinergic modulation of dentate gyrus processing through dynamic reconfiguration of inhibitory circuits

The dentate gyrus (DG) of the hippocampus plays a key role in memory formation, and it is known to be modulated by septal projections. By performing electrophysiology and optogenetics, we evaluated the role of cholinergic modulation in the processing of afferent inputs in the DG. We show that mature granule cells (GCs), but not adult-born immature neurons, have increased responses to afferent perforant path stimuli upon cholinergic modulation. This is due to a highly precise reconfiguration of inhibitory circuits, differentially affecting Parvalbumin and Somatostatin interneurons, resulting in a nicotinic-dependent perisomatic disinhibition of GCs. This circuit reorganization provides a mechanism by which mature GCs could escape the strong inhibition they receive, creating a window of opportunity for plasticity. Indeed, coincident activation of perforant path inputs with optogenetic release of acetylcholine produces a long-term potentiated response in GCs, essential for memory formation.