Neurodevelopmental disorder-associated Nr2f1 haploinsufficiency disrupts dentate gyrus inhibitory circuits and impairs short-term spatial memory

Abstract The dentate gyrus (DG) plays a central role in hippocampal information processing and spatial memory, functions that rely on a tightly regulated balance between excitation and inhibition, whose disruption is implicated in the pathophysiology of neurodevelopmental disorders. Here, we used adult constitutive Nr2f1 heterozygous knockout mice ( Nr2f1 +/− ) to investigate how Nr2f1 haploinsufficiency affects DG inhibitory circuit organization and function in a model of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a rare neurodevelopmental disorder associated with intellectual disability and learning impairment. Nr2f1 +/− mice showed impaired short-term spatial memory associated with increased recruitment of mature dentate granule cells and a shift in the synaptic excitatory/inhibitory balance toward excitation in the DG. Reduced GABAergic synaptic input was accompanied by decreased presynaptic vGAT levels and a reduced density of parvalbumin positive interneurons. Electrophysiological analyses revealed a substantial reorganization of inhibitory signaling, with reduced phasic inhibition coexisting with enhanced asynchronous GABA release and increased THIP-evoked tonic currents. These findings show that Nr2f1 haploinsufficiency differentially affects distinct modes of inhibition in the adult DG. Together, our results provide mechanistic insight into the cellular and synaptic alterations of DG inhibitory circuits that may contribute to cognitive impairment in BBSOAS with potential relevance to other neurodevelopmental disorders involving inhibitory circuit dysfunction.