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Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D‐deficient mice
Author(s) -
Shimizu Tokiko,
Hayashi Yoshinori,
Yamasaki Ryo,
Yamada Jun,
Zhang Jian,
Ukai Kiyoharu,
Koike Masato,
Mine Kazunori,
Von Figura Kurt,
Peters Christoph,
Saftig Paul,
Fukuda Takaichi,
Uchiyama Yasuo,
Nakanishi Hiroshi
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03250.x
Subject(s) - glutamate decarboxylase , hippocampal formation , pyramidal cell , gabaergic , hippocampus , glutamate receptor , chemistry , subiculum , entorhinal cortex , neuroscience , axon , biology , endocrinology , medicine , dentate gyrus , inhibitory postsynaptic potential , biochemistry , enzyme , receptor
Although of clinical importance, little is known about the mechanism of seizure in neuronal ceroid lipofuscinosis (NCL). In the present study, we have attempted to elucidate the mechanism underlying the seizure of cathepsin D‐deficient (CD–/–) mice that show a novel type of lysosomal storage disease with a phenotype resembling late infantile NCL. In hippocampal slices prepared from CD–/– mice at post‐natal day (P)24, spontaneous burst discharges were recorded from CA3 pyramidal cells. At P24, the mean amplitude of IPSPs after stimulation of the mossy fibres was significantly smaller than that of wild‐type mice, which was substantiated by the decreased level of γ‐aminobutyric acid (GABA) contents in the hippocampus measured by high‐performance liquid chromatography (HPLC). At this stage, activated microglia were found to accumulate in the pyramidal cell layer of the hippocampal CA3 subfield of CD–/– mice. However, there was no significant change in the numerical density of GABAergic interneurons in the CA3 subfield of CD–/– mice at P24, estimated by counting the number of glutamate decarboxylase (GAD) 67‐immunoreactive somata. In the hippocampus and the cortex of CD–/– mice at P24, some GABAergic interneurons displayed extremely high somatic granular immunoreactivites for GAD67, suggesting the lysosomal accumulation of GAD67. GAD67 levels in axon terminals abutting on to perisomatic regions of hippocampal CA3 pyramidal cells was not significantly changed in CD–/– mice even at P24, whereas the total protein levels of GAD67 in both the hippocampus and the cortex of CD–/– mice after P24 were significantly decreased as a result of degradation. Furthermore, the recombinant human GAD65/67 was rapidly digested by the lysosomal fraction prepared from the whole brain of wild‐type and CD–/– mice. These observations strongly suggest that the reduction of GABA contents, presumably because of lysosomal degradation of GAD67 and lysosomal accumulation of its degraded forms, are responsible for the dysfunction of GABAergic interneurons in the hippocampal CA3 subfield of CD–/– mice.