Fenfluramine Attenuates Retinal Microglial Activation but Does Not Rescue Structural and Vascular Deficits in a Rat Model of Dravet Syndrome

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency. While brain pathology has been extensively studied, the retina remains underexplored. This study investigated retinal structural, functional, vascular, and cellular changes in a Scn1a+/− rat model of DS. Anatomical quantification revealed thinning of the retinal nerve fiber layer and thickening of the outer plexiform layer. Electroretinography (ERG) showed selectively reduced oscillatory potential amplitudes, suggesting dysfunction of neurovascular coupling. Consistent with these findings, immunohistochemistry demonstrated aberrant vascular morphology, including increased vessel curvature and reduced branching density. In addition, we observed robust microglial activation in the outer and inner plexiform layers; however, astrocyte morphology remained largely unchanged. Fenfluramine, an approved anti-seizure drug for DS, attenuated microglial activation but failed to rescue retinal structural or vascular deficits, indicating a dissociation between its anti-inflammatory and disease-modifying effects. Our findings suggest that multimodal retinal assessment could serve as a noninvasive biomarker platform for monitoring disease progression and therapeutic response in DS.