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In the present study, we have attempted to elucidate the mechanism underlying the seizure of cathepsin\u2003D\u2010deficient (CD\u2013\/\u2013) mice that show a novel type of lysosomal storage disease with a phenotype resembling late infantile NCL. In hippocampal slices prepared from CD\u2013\/\u2013 mice at post\u2010natal day\u2003(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\u2010type mice, which was substantiated by the decreased level of \u03b3\u2010aminobutyric acid (GABA) contents in the hippocampus measured by high\u2010performance liquid chromatography (HPLC). At this stage, activated microglia were found to accumulate in the pyramidal cell layer of the hippocampal CA3 subfield of CD\u2013\/\u2013 mice. However, there was no significant change in the numerical density of GABAergic interneurons in the CA3 subfield of CD\u2013\/\u2013 mice at P24, estimated by counting the number of glutamate decarboxylase (GAD)\u200367\u2010immunoreactive somata. In the hippocampus and the cortex of CD\u2013\/\u2013 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\u2013\/\u2013 mice even at P24, whereas the total protein levels of GAD67 in both the hippocampus and the cortex of CD\u2013\/\u2013 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\u2010type and CD\u2013\/\u2013 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\u2013\/\u2013 mice.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2005.03250.x","type":"journal-article","created":{"date-parts":[[2005,7,15]],"date-time":"2005-07-15T16:54:18Z","timestamp":1121446458000},"page":"680-690","source":"Crossref","is-referenced-by-count":20,"title":["Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D\u2010deficient mice"],"prefix":"10.1111","volume":"94","author":[{"given":"Tokiko","family":"Shimizu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinori","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyoharu","family":"Ukai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Koike","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazunori","family":"Mine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kurt","family":"Von Figura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Peters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Saftig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaichi","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Uchiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,6,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-0102(01)00320-0"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(91)90159-L"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.1898"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.12.6496"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.12.1421"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000041913.97883.8B"},{"key":"e_1_2_7_8_1","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.1523\/JNEUROSCI.19-07-02556.1999","article-title":"Apparent loss and hypertrophy of interneurons in a mouse model of neuronal ceroid lipofuscinosis: evidence for partial response to insulin\u2010like growth factor\u20101 treatment","volume":"19","author":"Cooper J. 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