The role of Growth Associated Protein 43 (GAP-43) in epileptogenesis.

摘要

Epilepsy is the fourth most common neurological disorder in the United States. Although various treatments are available, there is no known cure. Additionally, 30-40% of patients do not respond to currently available antiepileptic therapies. This may be due to our lack of understanding of the underlying mechanisms causing epilepsy and its progression. Through investigating the cellular and molecular changes associated with epilepsy, it is possible to develop new strategies to properly diagnose, treat, monitor progression, and potentially cure epilepsy. Medical intractability within epilepsy is commonly associated with a brain pathology called Cortical Dysplasia (CD), a malformation in the cortex caused by abnormal neurodevelopment. In this work, we show an increased risk of epilepsy in a rat model of CD after traumatic brain injury (TBI) and injection of chemoconvulsant drugs. This result coincides with clinical reports suggesting that CD is an underlying risk factor of chronic epilepsy. It has been shown that Growth Associated Protein 43 (GAP-43), a growth protein that is highly expressed during brain development, is elevated in human CD brain tissue (Ying et al., 2014). In this dissertation, GAP-43 is investigated within CD and normal (non-CD) conditions throughout the course of epilepsy. In parallel to previous findings in human tissue, GAP-43 expression is elevated in CD rat brains, and is increased in response to an insult or an acutely induced seizure.;Remarkably, the expression of GAP-43 decreases to baseline levels over time in non-CD brain tissue, but continuously increases in CD brains until spontaneous seizures are observed. Moreover, serum GAP-43 levels are highest in rats that develop spontaneous epilepsy, supporting its use as a biomarker of disease progression. Finally, using a lentiviral vector containing shRNA against GAP-43, we have shown a significant decrease in acutely induced seizure duration and severity, as well as chronic interictal spiking, suggesting inhibition of epileptogenesis.;Together, these results provide new insight into the important role of GAP-43 within epilepsy and its progression, and advocate it as a novel target protein for diagnosis, treatment and prevention of epileptogenesis within CD.