RRC ID 60694
Author Nishitani A, Nagayoshi H, Takenaka S, Asano M, Shimizu S, Ohno Y, Kuramoto T.
Title Involvement of NMDA receptors in tremor expression in Aspa/Hcn1 double-knockout rats.
Journal Exp Anim
Abstract We recently demonstrated that aspartoacylase (Aspa) and hyperpolarized-activated cyclic nucleotide-gated potassium channel 1 (Hcn1) genes were causative of essential tremor (ET) in rats. This finding was obtained using Aspaem34Kyo/Hcn1A354V double-mutant rats, but they were bred on a heterogeneous genetic background of two strains, F344 and WTC. Here, we developed an Aspaem34Kyo/Hcn1em1Kyo double-knockout rat strain with a homogenous F344 genetic background and studied the ability of glutamate receptor antagonists to suppress ET. The F344-Aspa/Hcn1 double-knockout rats exhibited spontaneous, intense body tremor equivalent to that in the double-mutant rats. N-acetyl-aspartate (NAA), a substrate of ASPA, showed accumulation in all brain regions and in the spinal cord. However, N-acetyl-aspartyl-glutamate (NAAG), which is derived from NAA and interacts with glutamatergic receptors, was decreased in the medulla oblongata of the double-knockout rats. The tremor was suppressed by 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid, an N-methyl-D-aspartate (NMDA) receptor antagonist, in F344-Aspa/Hcn1 double-knockout rats. The non-NMDA glutamate receptor antagonist NBQX weakly inhibited the tremor, while the metabotropic glutamate receptor antagonist LY341495 showed no effect. In addition, both NR2B subunit-specific (Ro 25-6981) and NR2C/NR2D subunit-specific (cis-piperidine dicarboxylic acid) NMDA receptor antagonists suppressed the tremor. These data indicated that the pathogenesis of tremor in Aspa/Hcn1 double-knockout rats involved ionotropic glutamate receptors, particularly NMDA receptors.
Volume 69(4)
Pages 388-394
Published 2020-11-12
DOI 10.1538/expanim.20-0025
PMID 32507787
PMC PMC7677080
MeSH Amidohydrolases / genetics* Amidohydrolases / metabolism Animals Brain / metabolism Essential Tremor / drug therapy Essential Tremor / genetics* Gene Knockout Techniques Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics* Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism Molecular Targeted Therapy Phenols / pharmacology Phenols / therapeutic use Piperidines / pharmacology Piperidines / therapeutic use Potassium Channels / genetics* Potassium Channels / metabolism Quinoxalines / pharmacology Quinoxalines / therapeutic use Rats, Inbred F344 Rats, Mutant Strains Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors* Receptors, N-Methyl-D-Aspartate / physiology* Spinal Cord / metabolism
IF 1.574
Rats F344-Aspaem34Kyo (StrainID=1207) F344-Hcn1em1Kyo (StrainID=1308)