Synaptic ultrastructural alterations in human focal cortical dysplasia: Insights from volume electron microscopy

Focal cortical dysplasia (FCD) is a developmental malformation of the cerebral cortex and a leading cause of drug-resistant epilepsy in children and young adults. Disruption of the excitation-inhibition (E-I) balance is a hallmark of neuronal hyperexcitability in FCD, yet the underlying synaptic ultrastructural changes remain poorly understood. This study aimed to investigate synaptic architecture and associated organelle alterations in epileptogenic cortex affected by FCD.

Using volume electron microscopy, we performed a detailed morphological assessment of synaptic density, size, and organelle distribution within synapses in the temporal cortical layer III of a patient with FCD. Comparative analyses were conducted between dysplastic and nondysplastic cortical regions.

The dysplastic cortex exhibited a lower density of excitatory synapses but contained unusually large excitatory synapses with an increased number of synaptic vesicles. Inhibitory synapses were positioned farther from the nearest excitatory synapses along distal dendrites, potentially reducing the effectiveness of shunting inhibition in the dysplastic area. Presynaptic boutons in the dysplastic region showed increased mitochondrial density and abnormal mitochondrial morphology, whereas the proportion of postsynaptic protrusions containing a spine apparatus was reduced. These changes suggest potential deficits in intracellular calcium handling, metabolic homeostasis, and synaptic plasticity in the epileptogenic cortex. Additionally, maladaptive myelination was a prominent feature in the dysplastic region.

This study identifies distinct synaptic and subcellular structural abnormalities in FCD that may contribute to E-I imbalance and neuronal hyperexcitability. These findings provide novel ultrastructural insights into the pathophysiology of FCD and may inform future therapeutic strategies targeting synaptic and metabolic dysfunction.