Epilepsy is a complex and multifactorial neurological disorder, and now it is widely appreciated that changes in synaptic transmission often lie at the core of this disease. This has led to an increased interest in the role of synaptic proteins in thi disease. The best example of this are synaptic proteins synapsins, the main focus of this application. In mice, the deletion of synapsin I or synapsin II proteins results in a strong epilepic phenotype, and clinical studies demonstrated that synapsin deficiency is also associated with idiopathic epilepsy in humans. It was suggested that excitatory/inhibitory imbalance is one of the possible causes of the observed overexcitability. The applicant's recent study supports this hypothesis by directly demonstrating that synapsin II deletion differentially affects glutamatergic and GABAergic transmission at hippocampal slices and that epileptiform activity in SynII(-) slices is likely to result from impaired inhibition. Interestingly, deletion of the synapsin bindin partner Rab3a can suppress the epileptic phenotype observed in synapsin II deleted animals. This is obviously a potentially important observation that could help identify novel targets for th treatment of epilepsy. The experiments proposed in this application should help clarify the synaptic mechanisms that underlie the epileptogenic effects of synapsin II deletion as well as the physiological basis for the anti- epileptogenic effects of Rab3a deletion.
The Specific Aim 1 proposes to investigate the role of synapsin II in the regulation of synchronous and asynchronous inhibitory transmission. Inhibitory asynchronous release following high-frequency discharges is thought to regulate epileptiform activity, and our preliminary data suggests that synapsin II deletion decreases the inhibitory asynchronous component in CA1 hippocampal interneurons. To elucidate the mechanism by which the deletion of synapsin II inhibits asynchronous release component, we will employ paired recordings of inhibitory transmission at hippocampal slices to rigorously examine synchronous and asynchronous quantal release at synapsin II deleted animals.
The Specific Aim 2 proposes to understand how Rab3a deletion modifies the effect of Syn II deletion on synchronous and asynchronous inhibitory transmission. Since the deletion of Rab3a can neutralize synapsin-dependent epileptic seizures, we propose to investigate the asynchronous release component in the Rab3a(-) and in the SynII(-)/Rab3a(-) double knockout (DKO) neurons. Our preliminary data suggests that Rab3a deletion can restore the inhibitory asynchronous component reduced by the deletion of synapsin II. To understand by how Rab3a deletion can rescue the SynII(-) phenotype, we will investigate systematically synchronous and asynchronous release component at Rab3(-) and SynII(-)/Rabs3(-) DKO hippocampal slices and test whether the Rab3a incorporation into the SynII(-)/Rab3a(-) synapses can restore the SynII(-) phenotype.

Public Health Relevance

Epilepsy is an important health concern and thus the search for better therapeutic strategies is also an important research priority. It is now well understood that proper balance between inhibitory and excitatory synapses is critical for the proper functioning of the nervous system and epilepsy often involves an imbalance between neuronal excitation and inhibition. In this proposal we will determine how Rab3a and synapsin II interaction to control inhibitory neurotransmission transmission. We hope this work will contribute to the search and design of novel strategies for the treatment and prevention of epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Whittemore, Vicky R
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Universidad Central Del Caribe
United States
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Feliciano, Pedro; Matos, Heidi; Andrade, Rodrigo et al. (2017) Synapsin II Regulation of GABAergic Synaptic Transmission Is Dependent on Interneuron Subtype. J Neurosci 37:1757-1771
Feliciano, Pedro; Andrade, Rodrigo; Bykhovskaia, Maria (2013) Synapsin II and Rab3a cooperate in the regulation of epileptic and synaptic activity in the CA1 region of the hippocampus. J Neurosci 33:18319-30