Amino Acid Neurotransmission and its Regulation by Valproate: Focus on Aspartate
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AbstractSynaptic 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.
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.
List of papers. Papers II and IV are removed from the thesis due to copyright restrictions.
Paper I: Holten AT, Morland C, Nordengen K, and Gundersen V. (2008). Vesicular release of L- and D-aspartate from hippocampal nerve terminals: immunogold evidence. The Open Neurosci. J. 2:51-58. Published under a Creative Commons Attribution Non-Commercial License.
Paper II: Morland C, Nordengen K, Larsson MD, Prolo LM, Reimer R, Gundersen V. (2011). Vesicular uptake and exocytosis of aspartate is independent of sialin. Submitted version, published as: Morland C, Nordengen K, Larsson M, Prolo LM, Farzampour Z, Reimer RJ, Gundersen V. Vesicular uptake and exocytosis of L-aspartate is independent of sialin. FASEB J. 2013 Mar;27(3):1264-74. doi:10.1096/fj.12-206300
Paper III: Morland C, Nordengen K, Gundersen V. (2012). Valproate causes reduction of the excitatory amino acid aspartate in nerve terminals. NOTICE: this is the author s version of a work that was accepted for publication in Neuroscience Letters. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in: Neurosci Lett. 2012 Oct 11;527(2):100-4. doi:10.1016/j.neulet.2012.08.042
Paper IV: Morland C, Boldingh KA, Iversen EG, Hassel B. (2004). Valproate is neuroprotective against malonate toxicity in rat striatum: an association with augmentation of high-affinity glutamate uptake. J Cereb Blood Flow Metab. 24:1226-34. doi:10.1097/01.WCB.0000138666.25305.A7