Noradrenergic-dependent restoration of visual discrimination in a mouse model ofSYNGAP1-related disorder

Atypical sensory processing in neurodevelopmental disorders contributes to cognitive, social, and behavioural disruptions, yet underlying neurophysiological mechanisms remain unclear. Using a mouse model ofSYNGAP1haploinsufficiency (HET), a common monogenic cause of intellectual disability and autism, we investigated visual processing deficits.SyngapHET mice exhibited impaired behavioural visual discriminability, associated with reduced coding precision for visual stimuli in the primary visual cortex (V1). Notably, intrinsic properties of V1 neurons and visual responses under anaesthesia were unaltered, suggesting behavioural state-dependent disruptions in awakeSyngapHET mice. Supporting this, both mice and individuals withSYNGAP1haploinsufficiency exhibited larger pupil size during visual stimulation, implicating neuromodulatory dysfunction. Targeting noradrenergic tone systemically with an α₂-adrenergic receptor agonist restored V1 coding precision inSyngapHET mice. Our findings reveal neuromodulatory dysregulation as a novel mechanism underlying sensory disruptions inSYNGAP1-related disorder, highlighting potential therapeutic targets for addressing sensory impairments in neurodevelopmental disorders.