Abstracts

Rationale: Growth associated protein 43 (GAP-43) is a neuronal presynaptic membrane-bound protein that has been shown to play critical roles in the formation of neuronal synapses and establishment neural circuitry in developmental brain, axonal sprouting and regeneration after injury in adult peripheral nervous system, and long term potentiation and modulating neurotransmtter release in mature brain. GAP-43 is expressed at high levels during development and regenerations and there is a sharp decline in GAP-43 level once synaptogenesis is complete. Cortical dysplasias (CDs), a neuronal migration disorder, are a prominent cause of medically intractable epilepsy. To explore abnormal synaptic formation and neuronal membrane remodeling in CDs, we investigated the pattern and level of GAP-43 expression in human epileptogenic dysplastic cortex in brain specimens surgically resected from 10 patients with medically intractable focal epilepsy due to CDs. Methods: We used immunohistochemical (IHC) staining to examine the cellular expression patterns of GAP-43 protein in dysplastic cortex and normal appearing cortex in 7 patients, and western blot techniques to quantify the GAP-43 protein level in 5 patients. For western blot study, the resected cortical tissues from each patient were grouped into epileptic and nonepileptic, as determined by prolonged subdural electrode recording or direct intraoperative electrocorticographic recording. The tissues from 2 patients were performed for both IHC staining and western blot analysis. Results: In all 7 patients that GAP-43 IHC was performed, GAP-43 stained neuropils (the tubular structures) were increased in the dysplastic gray matter as compared with the normal appearing cortex. The GAP-43 protein levels as determined by western blot were increased in the epileptic cortex as compared with nonepileptic cortex. Conclusions: Our current study by both immunohistochemistry and western blot is the first to show an increase in the GAP-43 protein in epileptic dysplastic cortex resected from patients with focal CDs. The increased GAP-43 proteins in the dysplastic regions as identified by IHC likely localized in the axonal terminals. The heavily GAP-43 stained tubular structures may also represent the myelin forming oligodentrocytes wrapped around the aberrant formed axons. These need to be confirmed by double labeling of GAP43 with neurofilament protein and myelin basic proteins in the future. These results suggest that GAP-43 associated abnormal axonal formation may underline on the cellular mechanisms that contribute to the altered neuronal communication which may mediated hypersynchronization of neuronal activity leading to seizure generation in focal cortical dysplasia