Synaptic and mitochondrial alterations in human focal cortical dysplasia: insight from volume electron microscopy

초록

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 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. 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 inhibition in the dysplastic area. There was an increase in mitochondrial density and altered mitochondrial morphology within presynaptic boutons, along with a decreased proportion of postsynaptic protrusions containing a spine apparatus. These changes suggest potential deficits in intracellular calcium handling, metabolic homeostasis, 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. Keywords: Cortex · Epilepsy · Hyperexcitability · Synapse · Mitochondria