NR2F1 HAPLOINSUFFICIENCY ALTERS DENTATE GYRUS INHIBITORY CONTROL AND SHORT-TERM SPATIAL MEMORY IN A BBSOAS NEURODEVELOPMENTAL DISORDER MOUSE MODEL

Pathogenic variants in the transcriptional regulator NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by intellectual disability, learning impairments and behavioral alterations. However, the neural and circuit-level mechanisms underlying the cognitive deficits associated with BBSOAS remain poorly understood. To address this, we used constitutive heterozygous knockout mice (Nr2f1+/-) to model Nr2f1 haploinsufficiency associated with BBSOAS. Using the novel object location task, we found that Nr2f1+/- mice exhibit impaired short-term spatial memory, consistent with deficits in hippocampal dentate gyrus (DG)-dependent processes such as fine spatial discrimination and pattern separation. This cognitive impairment was accompanied by an increased number of activated mature dentate granule cells and reduced GABAergic inhibitory input, indicating dysfunctional inhibitory control over excitatory granule neurons. At the synaptic level, GABAergic terminals displayed enhanced asynchronous release and prolonged tonic inhibition, together with an enrichment of extrasynaptic GABAA receptors. Together, our findings demonstrate that Nr2f1 haploinsufficiency disrupts the finely tuned inhibitory regulations required for DG-dependent cognitive functions and suggest that targeting inhibitory circuitry may offer a potential therapeutic strategy for BBSOAS.