Antiepileptic medication strengthens excitatory neurotransmission in pyramidal neurons of the adult human neocortex

Homeostatic synaptic plasticity serves to maintain neuronal function within a dynamic range upon perturbations in network activity. While coordinated structural and functional changes at synaptic sites play a crucial role in adaptive processes, the specific regulatory mechanisms and biological relevance of homeostatic plasticity in the human brain warrant further investigation. In this study, we investigated the effects of neural network silencing, achieved through pharmacological inhibition of voltage-gated sodium channels or glutamatergic neurotransmission - common targets of antiepileptic medication - on functional and structural properties of murine and human cortical tissue. Using mouse entorhino-hippocampal tissue cultures, acute neocortical slices of adult mice, and human brain tissue, we characterize homeostatic synaptic plasticity across models, brain regions, and species. Our findings demonstrate local homeostatic synaptic plasticity in the adult human neocortex, highlighting the potential effects of antiepileptic medication in brain regions unaffected by the primary diseases, which might represent a mechanism for neuropsychiatric effects linked to these medications and increased seizure susceptibility upon discontinuation of antiepileptic medication.