Microstructural Spine Alterations Increase Neuronal Excitability in Focal Cortical Dysplasia

Abstract Focal cortical dysplasia(FCD) is a leading cause of drug-resistant epilepsy, traditionally attributed to impaired inhibition. However, recent ultrastructural evidence suggests excitatory synaptic alterations may also contribute. To investigate this, we performed computational modeling of human pyramidal neurons in NEURON, incorporating electron microscopy–derived dendritic spine morphologies. Baseline and FCD-like models were constructed with differences in spine density and morphology while maintaining comparable net synaptic input. Simulations revealed that reduced spine density increased input resistance and amplified excitatory postsynaptic potentials, enhancing dendritic-to-somatic transmission. Spine neck geometry, but not head size, critically shaped voltage compartmentalization. The altered model required markedly fewer synchronous inputs to reach spiking threshold and exhibited higher firing rates under Poisson-distributed synaptic activity, particularly under sparse input conditions. These results demonstrate that excitatory microstructural changes - reduced spine density and weakened neck compartmentalization - can elevate neuronal excitability, in addition to the inhibitory deficit which is the biggest known effect. These findings highlight excitatory spine remodeling as another key driver of epileptogenesis. We speculate that extending this analysis will be essential to fully understand circuit-level hyperexcitability and to identify new therapeutic targets. Competing Interest Statement The authors have declared no competing interest.