Amino Acid Neurotransmission and its Regulation by Valproate: Focus on Aspartate

Abstract

Synaptic transmission requires packing of neurotransmitters into synaptic vesicles. The role of aspartate as a neurotransmitter has been debated for more than 30 years, as vesicular accumulation of aspartate has been difficult to prove. In this thesis I demonstrate that hippocampal synaptic vesicles are capable of aspartate uptake, and that release of aspartate from nerve terminals occurs through regulated exocytosis. Surprisingly, we show that the suggested vesicular aspartate transporter, sialin, was not important for the synaptic release of aspartate, indicating that aspartate accumulation in synaptic vesicles must involve a yet unidentified aspartate transporter.<br><br> Aspartate stimulates the NMDA-type of glutamate receptors, and thus has excitatory properties. In epilepsy, an imbalance between excitation and inhibition leads to excess activation of neurons. The antiepileptic drug, valproate, is effective in the treatment of a broad spectrum of epilepsies, yet its main mechanism of action remains unresolved. Here we show that valproate reduces the level of aspartate in nerve terminals, probably leading to reduced aspartergic neurotransmission. The resulting reduction in the excitation of neurons might underlie some of the antiepileptic effects of valproate. We further show that valproate treatment can lead to increased number of functional excitatory amino acid transporters in the rat brain, thereby decreasing the extracellular levels of aspartate and glutamate, which can protect neurons against excitotoxicity.