Synaptic Ultrastructural Alterations in Human Focal Cortical Dysplasia: Insights from Volume Electron Microscopy

Focal cortical dysplasia (FCD) is a developmental disorder of the cerebral cortex and a leading cause of drug-resistant epilepsy in children and young adults. A disrupted excitation-inhibition (E-I) balance is a hallmark of neuronal hyperexcitability in FCD, yet the underlying synaptic ultrastructural alterations remain poorly understood. 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 an FCD patient. Our quantitation revealed a reduced density of inhibitory (symmetric) synapses on pyramidal neuron cell bodies. Notably, the dysplastic region displayed a lower density of excitatory (asymmetric) synapses but contained extra-large excitatory synapses, which contained an increased number of synaptic vesicles. Additionally, inhibitory synapses were located further away from the nearest excitatory synapses along distal dendrites, possibly weakening the effectiveness of shunting inhibition in the dysplastic area. There was also a decrease in presynaptic boutons housing mitochondria and in postsynaptic protrusions containing a spine apparatus, pointing to potential deficits in intracellular calcium handling and synaptic plasticity in the epileptogenic area. Moreover, maladaptive myelination was a prominent feature in the dysplastic region. These findings collectively indicate that synaptic architectural modifications may contribute to the neuronal hyperexcitability associated with epilepsy in FCD.