UNRAVELING THE ALTERATIONS IN INHIBITION AND TOP-DOWN CONNECTIVITY UNDERLYING SENSORY-EVOKED HYPEREXCITATION IN FRAGILE X SYNDROME

Fragile X syndrome (FXS) is the most common single gene cause of autism spectrum disorder (ASD), and results from a mutation in the FMR1 gene located in the X chromosome. While most research in FXS has focused on excitatory neurons and fast-spiking inhibitory interneurons, the contribution of Layer 1 (L1) GABAergic interneurons, particularly neurogliaform cells, remains largely underexplored. Due to their strategic position and role as main recipients of bottom-up and top-down inputs, dysfunction of neurogliaform cells may contribute to the sensory hypersensitivity and the excitatory-inhibitory imbalance, characteristic of FXS.
Using whole cell patch clamp recordings and optogenetic manipulation of long-range inputs, we examined whether the loss of FMRP affects the intrinsic properties and synaptic connectivity of neurogliaform cells in the primary visual cortex across different genotypes. Results revealed alterations in intrinsic excitability, with heterozygous mutant females exhibiting increased responsiveness to depolarizing inputs, while complete loss of FMRP in males and homozygous females resulted in decreased intrinsic excitability. Preliminary data from optogenetic stimulation of axons originating from the anterior cingulate cortex suggests a potential weakening of top-down inputs in heterozygous mutant females. Our results suggest that FMRP loss disrupts both the intrinsic excitability and synaptic connectivity of neurogliaform cells, which may impair their function as integrators of sensory and modulatory input.