Aberrant synaptic transmission in the hippocampal CA3 region and cognitive deterioration in protein-repair enzyme-deficient mice.
L-aspartate is the amino-acid residue most susceptible to spontaneous isomerization. This denaturation causes an alteration in the biological activity of the protein and is regarded as an aging process of the protein. Protein L-isoaspartyl methyltransferase (PIMT) repairs this post-translational modification and thus is implicated in retarding the aging process of proteins. PIMT is highly expressed in the brain, and its deficiency results in progressive epilepsy after 4 weeks of age, with a fatal seizure in mice. Here we report the pathophysiological role of this repair system in the hippocampal slice of PIMT-deficient mice. The hippocampal mossy fiber-CA3 synapses of PIMT-deficient mice showed hyperexcitation that was repressed by a gamma-aminobutyric acid (GABA)A receptor agonist muscimol. In addition, the mossy fiber-CA3 synapses failed to show long-term potentiation or paired-pulse facilitation. No abnormality, however, was observed in Schaffer collateral-CA1 synapses or in perforant path-dentate gyrus synapses. Electron microscopic study revealed aberrant distribution of synaptic vesicles in the mossy fiber terminals and vacuolar degeneration at the axon hillock of dentate granule cells in PIMT-deficient mice. Furthermore, the PIMT-deficient mice showed impaired spatial memory in Morris water maze test and exhibited fewer anxiety-related behaviors in the elevated-plus test. These results suggest that the mossy fiber-CA3 system is vulnerable to aspartate isomerization and that the PIMT-mediated repair system is essential for maintenance of normal functions of the hippocampus.
Ikegaya
Y
Y
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Yamada
M
M
Fukuda
T
T
Kuroyanagi
H
H
Shirasawa
T
T
Nishiyama
N
N
D000375:Aging / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000378:metabolism; D004827:Epilepsy / Q000378:metabolism; D007536:Isomerism; D017774:Long-Term Potentiation / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D019599:Mossy Fibers, Hippocampal / Q000201:enzymology* / Q000648:ultrastructure; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D011489:Protein Denaturation; D013569:Synapses / Q000201:enzymology; D009435:Synaptic Transmission / Q000502:physiology*
D001224:Aspartic Acid; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase