Excitatory amino acid (EAA)-mediated neurotransmission is widespread throughout the mammalian CNS and is involved in many important functions during neurodevelopment, synaptic plasticity, and neuropathology. Two EAAs, L-glutamate (Glu) and L-aspartate (Asp), fulfill most of the criteria for endogenous neurotransmitters in various regions of the CNS, including the hippocampus and the cerebellum. However, the mechanisms responsible for Asp-mediated neuronal responses, unlike those mediated by Glu, are largely unexplored. Although Asp is a highly selective NMDA receptor agonist in hippocampal neurons, Asp was found to activate a distinct response in Purkinje cells from genetically modified mice that lack functional NMDA receptors. Thus, Purkinje cells may express a novel receptor that is specifically activated by Asp. The goal of this application is to characterize this unique Asp response and to identify its functional role in Purkinje cells. In the first specific aim, the Asp response will be characterized using electrophysiological and pharmacological approaches in cultured Purkinje cells. The sensitivity of the Asp response to agonists and antagonists of known EAA receptors will be determined, and efforts will be made to define antagonists specific for the Asp response. Single channel properties of Asp responses will also be investigated. In the second aim, these properties will be used to investigate the role of the putative Asp receptor in synaptic transmission at climbing fiber- and parallel fiber-Purkinje cell synapses in cerebellar slices. The role of the Asp receptor in synaptic plasticity will also be analyzed. In the third aim, as a first step to identify the putative Asp receptor, glutamate receptor subtypes expressed in Purkinje cells will first be identified. Those subtypes, including several splice variants and RNA editing variants, will be co-expressed in heterologous cells to test whether they can reconstitute the Asp response. Further, two complementary approaches will be taken. A sequence similarity strategy will be pursued that takes advantage of possible functional similarities between the Asp response and glutamate receptor-mediated responses. In addition, expression cloning approaches will be taken that utilize the pharmacological profile of the Asp response to identify potential Asp receptors. The results of these studies will clarify the nature of the unique Asp response in Purkinie cells. Moreover, since Asp may function as a neurotransmitter in other regions of the CNS, the results will provide a better understanding of the general role of Asp in neurotransmission and in the pathogenesis of certain brain disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-4 (01))
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Talley, Edmund M
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St. Jude Children's Research Hospital
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Hirai, Hirokazu; Miyazaki, Taisuke; Kakegawa, Wataru et al. (2005) Rescue of abnormal phenotypes of the delta2 glutamate receptor-null mice by mutant delta2 transgenes. EMBO Rep 6:90-5
Matsuda, Shinji; Hannen, Rosalind; Matsuda, Keiko et al. (2004) The C-terminal juxtamembrane region of the delta 2 glutamate receptor controls its export from the endoplasmic reticulum. Eur J Neurosci 19:1683-90
Matsuda, Keiko; Fletcher, Matt; Kamiya, Yoshinori et al. (2003) Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors. J Neurosci 23:10064-73
Wang, Ying; Matsuda, Shinji; Drews, Valerie et al. (2003) A hot spot for hotfoot mutations in the gene encoding the delta2 glutamate receptor. Eur J Neurosci 17:1581-90
Yuzaki, Michisuke (2003) The delta2 glutamate receptor: 10 years later. Neurosci Res 46:11-22
Yuzaki, Michisuke (2003) New insights into the structure and function of glutamate receptors: the orphan receptor delta2 reveals its family's secrets. Keio J Med 52:92-9
Kohda, Kazuhisa; Kamiya, Yoshinori; Matsuda, Shinji et al. (2003) Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors. Brain Res Mol Brain Res 110:27-37
Hirai, Hirokazu; Launey, Thomas; Mikawa, Sumiko et al. (2003) New role of delta2-glutamate receptors in AMPA receptor trafficking and cerebellar function. Nat Neurosci 6:869-76
Matsuda, Keiko; Kamiya, Yoshinori; Matsuda, Shinji et al. (2002) Cloning and characterization of a novel NMDA receptor subunit NR3B: a dominant subunit that reduces calcium permeability. Brain Res Mol Brain Res 100:43-52
Matsuda, Shinji; Yuzaki, Michisuke (2002) Mutation in hotfoot-4J mice results in retention of delta2 glutamate receptors in ER. Eur J Neurosci 16:1507-16

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