N-acetyl-L-aspartate activates hippocampal CA3 neurons in rodent slice preparations.
High N-acetyl-L-aspartate (NAA) levels prevail as a free amino acid in vertebrate brains. NAA is synthesized from aspartate and acetyl Co-A, or is liberated by the hydrolyzation of N-acetyl-L-aspartyl-glutamate in mitochondria before being metabolized by aspartoacylase to aspartate and acetate in the cytosol of glial cells. The tremor rat (tm/tm), derived from a Kyoto-Wistar colony, shows absence-like seizures with 5- to 7-Hz spike-wave-like complexes in cortical and hippocampal electroencephalograms (EEG). Genomic microdeletion was found within the aspartoacylase-encoding tm critical region, where an increase in the NAA level was noted. Intracerebroventricular NAA induced absence-like seizures, convulsive seizures or both in epileptic EEG of Wistar rats. NAA activated the hippocampal CA3 neurons of Wistar rats via the metabotropic glutamate receptor (mGluR) in acutely dissociated hippocampal CA3 neurons. The mechanism of NAA action on CA3 neurons was examined with intracellular recording of Wistar and tremor rat hippocampal slices to evaluate the role of NAA in neuronal networks. Bath application of NAA (10 microM-1mM) dose-dependently induced depolarization in CA3 neurons of Wistar and tremor rats. Cadmium (a Ca(2+) channel antagonist) and GDEE (an ionotropic glutamate receptor antagonist) did not affect NAA-induced depolarization. Although ACPD (a nonspecific mGluR agonist) induced similar depolarizations in CA3 neurons, MCPG (a mGluR antagonist) inhibited NAA-induced depolarization. These results suggest that NAA probably activates hippocampal CA3 neurons via the mGluR in a neuronal network.
Hanaya
R
R
Department of Neurosurgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. hanaya@hiroshima-u.ac.jp
Kiura
Y
Y
Kurisu
K
K
Sakai
N
N
Serikawa
T
T
Sasa
M
M
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005971:Glutamates / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects*; D019599:Mossy Fibers, Hippocampal / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014202:Tremor / Q000473:pathology
D004148:Dioxolanes; D005971:Glutamates; D011687:Purines; C474696:methyl-(4-carboxyphenyl)glycine; D002104:Cadmium; C060939:dineopentyl glutamate; C104068:4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolane-2-methanol; D001224:Aspartic Acid; C000179:N-acetylaspartate; D005998:Glycine