Microstructural spine alterations increase neuronal excitability in focal cortical dysplasia Type I.

Introduction: Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy and has predominantly been associated with impaired inhibitory signaling. However, recent ultrastructural studies have identified morphological alterations in excitatory synapses, suggesting that structural changes in excitatory connectivity may also contribute to cortical hyperexcitability. Methods: We used biophysically grounded computational models of human cortical pyramidal neurons to investigate how disease-associated alterations in dendritic spine architecture affect neuronal excitability. Spine density and spine geometry were independently manipulated based on quantitative volume electron microscopy measurements, allowing us to distinguish the contributions of individual structural features of excitatory synapses. Results: Reduced spine density and altered spine neck geometry increased neuronal excitability through complementary mechanisms, whereas variations in spine head size had comparatively minor effects. These structural alterations differentially influenced synaptic signal propagation and spike initiation. Their combined effects substantially increased neuronal output, particularly under conditions of sparse synaptic input. Discussion: These findings identify excitatory synaptic microstructure as an independent and mechanistically distinct contributor to hyperexcitability in FCD Type I. By linking ultrastructural abnormalities to altered neuronal input-output function, this study supports a potential contribution of excitatory synaptic alterations to the pathophysiology of FCD.