Decreased synaptic GABAergic inhibition in the dentate gyrus of a mouse model of the neurodevelopmental disorder BBSOAS

The Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS; OMIN#615722), is a rare neurodevelopmental disorder caused by mutations in the NR2F1 gene, a transcriptional regulator playing pleiotropic functions in brain development. Most NR2F1 pathological variants are deletions and/or mutations leading to haploinsufficiency or dominant negative effects. Although BBSOAS is characterized by a wide array of clinical features, intellectual disability (ID), visual impairment, and autism spectrum disorder (ASD) are predominant. Notably, NR2F1 is identified as a risk gene for ASD (SFARI database), suggesting its involvement in related disorders. Alterations in postnatal hippocampal neurogenesis have been reported in animal models of ASD/ID and recent findings suggest that a deficit in hippocampal plasticity may contribute to BBSOAS.Here, to investigate the impact of Nr2f1 haploinsufficiency on the hippocampal circuit, we took advantage of constitutive Nr2f1 heterozygous mice (i.e., Nr2f1-HET), a recently validated BBSOAS mouse model, and focussed on the adult dentate gyrus (DG), crucial for cognitive processes (e.g., learning and memory).Our in situ analyses on the DG of Nr2f1-HET mice revealed morphological alterations in adult-born immature neurons with phenotypes typical of pathological conditions, along with altered hippocampal circuit activation. Furthermore, we observed increased expression of immediate early genes (e.g., Npas4, c-fos) and reduced frequency in mini inhibitory postsynaptic currents (mIPSCs) in mature granule cells; together with diminished expression of the presynaptic marker VGAT, these data suggest decreased synaptic inhibition. These findings underscore the involvement of hippocampal dysfunction in BBSOAS and suggest a potential mechanism underlying cognitive impairments in affected individuals.