FMRP restoration in parvalbumin interneurons: A circuit-specific improvement of visual learning in fragile X syndrome

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired sensory processing and learning disabilities, of which Fragile X syndrome (FX) is a leading genetic cause. Visual familiarity evokes persistent theta oscillations (4-8 Hz) in the primary visual cortex (V1) of mice, which are weaker and slower in <i>Fmr1</i> KO mice correlating with the decreased excitatory synaptic drive onto fast-spiking interneurons. To test if loss of <i>Fmr1</i> protein (FMRP) expression in parvalbumin-positive (PV+) fast-spiking interneurons is causal to impaired oscillations and learning, we restored FMRP selectively in PV+ interneurons (<i>Fmr1</i>cON/PV-Cre). Silicon probe recordings of V1 showed that targeted restoration rescued frequency and duration of oscillatory responses and improved direction tuning deficits seen in FX. These mice also exhibited improved performance in a visual learning task and decreased hyperactivity. Our findings support an important role of PV+ interneurons in visual learning and memory, suggesting promising avenues for circuit-specific therapeutic interventions in FX syndrome.