Long-Term Modulation of Cortical Excitability by Repeated Anodal Transcranial Direct Current Stimulation Highlights Neurobiological Constraints in a Neurodevelopmental Disorder Model

Introduction Transcranial direct current stimulation (tDCS) modulates neuronal excitability, but its long-term effects on intrinsic and synaptic properties remain largely underinvestigated, as are its effects in the case of a malfunctioning brain, such as in neurodevelopmental disorders. Materials and Methods We applied a repeated sham or anodal tDCS for five consecutive days to wild-type (WT) and Angelman syndrome (AS) model mice over the parietal cortex. Behavioral assessments began on the third day of stimulation. Ninety minutes after the final fifth session, we extracted the brains and measured the intrinsic and synaptic neuronal properties of layer-V pyramidal neurons in the cortical area under the stimulating electrode. Results Anodal tDCS did not improve spatial memory performance in the object location memory task but altered exploratory behavior. Moreover, it differentially modulated neuronal excitability in WT and AS mice, inducing an enhanced excitability, especially in AS neurons. In addition, we observed complementary differential effects of anodal tDCS on the intrinsic properties of WT and AS neurons. Although WT neurons showed homeostatic regulatory modulation of intrinsic and synaptic properties that mitigated the enhanced excitability to some extent, AS neurons showed a dysregulated increase in excitability, with impaired compensatory mechanisms at both intrinsic and synaptic levels. Discussion These findings reveal that tDCS modulates excitability by inducing long-term modulation of intrinsic and synaptic properties. Moreover, these findings emphasize that the neurophysiologic response to tDCS is shaped by the underlying neurobiological context, differing markedly between healthy and diseased brains. Conclusions Although tDCS can induce long-term excitability changes, its effects depend on intact regulatory mechanisms, highlighting the need for tailored approaches in neurodevelopmental disorders such as AS.