Epilepsy is one of the most common chronic neurological disorders. Despite this up to 30% of patients remain inadequately treated even with optimized management, indicating the need for novel therapeutic approaches. The aberrant neuronal activity that underlies seizures requires the rapid synthesis, packaging and release of glutamate and GABA, the primary excitatory and inhibitory neurotransmitters. While it has been demonstrated that the majority of glutamate recycling, and a smaller, but significant portion of GABA recycling in the mammalian brain is normally mediated by a neuronal-glial glutamate-glutamine shuttle, the role of this mechanism in epilepsy and its potential as a therapeutic site for the disease remains unclear. Preliminary data for the proposal indicates that pharmacological inhibition of SAT1, a neuronal glutamine transporter and a putative component of this shuttle, attenuates epileptiform activity. Our data further demonstrates that SAT1 and two related transporters are upregulated in two animal models of epileptogenesis. The primary hypothesis of the proposed research is that an increase flux through the glutamate-glutamine shuttle occurs during seizures, and that compensatory upregulation of the molecular constituents of the shuttle are required for epileptogenesis.
The specific aims are 1) to determine if SAT1 transporter activity is integral to the glutamate-glutamine shuttle and then determine if its activity or the activity of the glutamate-glutamine shuttle is upregulated in animal models of epileptogenesis; and 2) determine if the expression of other components of the glutamate-glutamine shuttle are upregulated during epileptogenesis. The proposed experiments to accomplish these aims include the use of radiotracer studies to characterize SAT1 activity in normal and epileptogenic tissue, the use of NMR with isotopically labeled glucose to analyze flux through the glutamate-glutamine shuttle in normal and epileptogenic tissue, and in situ and immunostaining studies to characterize the expression of the molecular components of the shuttle in models of epileptogenesis. Progress in these aims will advance the understanding of glutamine transport in amino acid neurotransmitter recycling and determine the potential role for the glutamate-glutamine shuttle as pharmacological target in the treatment of epilepsy. ? ?
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