Growth Associated Protein 43 (GAP-43) as a Novel Target for the Diagnosis, Treatment and Prevention of Epileptogenesis

Ashley D Nemes,Qi-Gang Zhou,Zhong Ying,Hoonkyo Suh,Imad M Najm,Katayoun Ayasoufi

doi:10.1038/s41598-017-17377-z

Abstract

We previously showed increased growth associated protein 43 (GAP-43) expression in brain samples resected from patients with cortical dysplasia (CD), which was correlated with duration of epilepsy. Here, we used a rat model of CD to examine the regulation of GAP-43 in the brain and serum over the course of epileptogenesis. Baseline GAP-43 expression was higher in CD animals compared to control non-CD rats. An acute seizure increased GAP-43 expression in both CD and control rats. However, GAP-43 expression decreased by day 15 post-seizure in control rats, which did not develop spontaneous seizures. In contrast, GAP-43 remained up-regulated in CD rats, and over 50% developed chronic epilepsy with increased GAP-43 levels in their serum. GAP-43 protein was primarily located in excitatory neurons, suggesting its functional significance in epileptogenesis. Inhibition of GAP-43 expression by shRNA significantly reduced seizure duration and severity in CD rats after acute seizures with subsequent reduction in interictal spiking. Serum GAP-43 levels were significantly higher in CD rats that developed spontaneous seizures. Together, these results suggest GAP-43 as a key factor promoting epileptogenesis, a possible therapeutic target for treatment of progressive epilepsy and a potential biomarker for epilepsy progression in CD.

Highlights

Congenital focal brain malformations known as cortical dysplasia (CD) are common pathological substrates of medically intractable epilepsies
We recently demonstrated that growth associated protein 43 (GAP-43) proteins are higher in the dysplastic and epileptic cortex compared to normal appearing cortex in human patients with medically intractable epilepsy who underwent surgical resections[14]
Our results show that a “second hit” in rats with CD leads to long-lasting upregulation of new synapse protein formation (GAP-43) in predominantly excitatory synapses

Summary

Introduction

Congenital focal brain malformations known as cortical dysplasia (CD) are common pathological substrates of medically intractable epilepsies. The first seizure is typically followed by a latent period, leading to seizure recurrence and the development of drug resistance in some patients. These observations suggest that epilepsy is a non-static disease, and the epileptic brain region may continue to undergo progressive cellular and molecular changes over time. Our results suggest the interesting possibility that GAP-43 is upregulated after a second hit (e.g. seizure), leading to the formation of highly interconnected, synchronized epileptic neural networks. The findings presented in this study provide valuable insight into some possible molecular mechanisms of epileptogenesis and identify GAP-43 as a potential new target protein for the treatment and prevention of epilepsy in cortical dysplasia

Methods

Results

Conclusion