EXPLORING PATHOGENIC MECHANISMS OF BBSOAS NEURODEVELOPMENTAL DISORDER: INSIGHTS FROM THE ADULT MOUSE DENTATE GYRUS NEURO- GENIC NICHE

OMIN#615722) is a rare neurodevelopmental disorder caused by mutations in the NR2F1 gene, a transcriptional regulator with pleiotropic functions in brain development1. NR2F1 mutations often result in haploinsufficiency or dominant negative effects, but their biological consequences remain poorly understood. The spectrum of BBSOAS includes intellectual disability (ID), visual impairment and autistic traits. Interestingly, alterations in postnatal dentate gyrus (DG) hippocampal neurogenesis have been reported in several animal models of autism or ID2. In our laboratory, we are investigating the role of NR2F1 in the adult DG by combining mouse genetics, genome-wide and in silico analyses with neu- roanatomical and imaging approaches3,4. Our study revealed a novel regulatory role for NR2F1 in mitochondria. Loss of NR2F1 function in the adult mouse DG results in reduced mitochondrial mass, mitochondrial fragmentation and downregulation of key mitochondrial proteins in newborn neurons, affecting their gene- sis, survival and integration4. Nr2f1 heterozygous mice, in parallel with the dysregulation of several nuclear-encoded mitochondrial genes and proteins, show impaired morphology, altered circuit activation and reduced synaptic inhibition in mature DG granule neurons. These findings underscore hippocampal dysfunction in BBSOAS and reveal potential mechanisms contributing to the associated cognitive impairment.