Neural stem cell–specific ITPA deficiency causes neural depolarization and epilepsy

Yuichiro Koga, Daisuke Tsuchimoto, Yoshinori Hayashi, Nona Abolhassani, Yasuto Yoneshima, Kunihiko Sakumi, Hiroshi Nakanishi, Shinya Toyokuni, Yusaku Nakabeppu

研究成果: Contribution to journalArticle査読

抄録

Inosine triphosphate pyrophosphatase (ITPA) hydrolyzes inosine triphosphate (ITP) and other deaminated purine nucleotides to the corresponding nucleoside monophosphates. In humans, ITPA deficiency causes severe encephalopathy with epileptic seizure, microcephaly, and developmental retardation. In this study, we established neural stem cell–specific Itpa–conditional KO mice (ItpacKO mice) to clarify the effects of ITPA deficiency on the neural system. The Itpa-cKO mice showed growth retardation and died within 3 weeks of birth. We did not observe any microcephaly in the Itpa-cKO mice, although the female Itpa-cKO mice did show adrenal hypoplasia. The Itpa-cKO mice showed limb-clasping upon tail suspension and spontaneous and/or audiogenic seizure. Whole-cell patch-clamp recordings from entorhinal cortex neurons in brain slices revealed a depolarized resting membrane potential, increased firing, and frequent spontaneous miniature excitatory postsynaptic current and miniature inhibitory postsynaptic current in the Itpa-cKO mice compared with ITPA-proficient controls. Accumulated ITP or its metabolites, such as cyclic inosine monophosphates, or RNA containing inosines may cause membrane depolarization and hyperexcitability in neurons and induce the phenotype of ITPA-deficient mice, including seizure.

本文言語英語
論文番号e140229
ジャーナルJCI Insight
5
22
DOI
出版ステータス出版済み - 11 19 2020

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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