Anodal Transcranial Direct Current Stimulation Improves Social Behavior Alongside Neuroplastic Changes in a Tsc2^+/-...

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by altered synaptic connectivity and network organization, resulting in profound impairments in social communication and interaction. Transcranial direct current stimulation (tDCS) represents a promising approach to modulate maladaptive plasticity associated with ASD; however, mechanistic evidence from preclinical models remains limited. Here, we investigated whether repeated anodal tDCS targeting the medial prefrontal cortex modulates ASD-relevant social behavioral deficits in a rodent model. Male Tsc2^+/- rats with induced developmental status epilepticus (DSE) and wild-type (WT) littermate controls received repeated anodal tDCS (200 μA for 20 min, twice daily) for 12 consecutive days. Social behavior profiles were evaluated at baseline and at 2- and 5 weeks following treatment. In addition, postmortem analyses investigated neuroplasticity-related markers and monoaminergic neurotransmitter levels. tDCS selectively modulated social behavioral deficits in Tsc2^+/- DSE rats. Specifically, tDCS in Tsc2^+/- DSE rats caused a sustained reduction in social avoidance and transient improvements in social exploration, while social approach behavior improved but did not return to WT levels, and social recognition impairments remained unaffected. In addition, tDCS restored abnormal serotonin levels in brain regions involved in social behavior, suggesting a potential contribution of serotonergic mechanisms to the observed behavioral effects. Our results demonstrate that improvements in some domains of ASD-relevant social deficits following tDCS persist for weeks beyond the stimulation period, possibly through neuroplastic modulation of serotonergic neurotransmission. Together, these results provide mechanistic insights into how noninvasive brain stimulation may modulate specific components of social dysfunction and highlight the importance of considering the multidimensional nature of ASD-related behaviors when evaluating therapeutic interventions.