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

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 th...

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Bibliographic Details
Published in:JCI insight 2020-11, Vol.5 (22)
Main Authors: Koga, Yuichiro, Tsuchimoto, Daisuke, Hayashi, Yoshinori, Abolhassani, Nona, Yoneshima, Yasuto, Sakumi, Kunihiko, Nakanishi, Hiroshi, Toyokuni, Shinya, Nakabeppu, Yusaku
Format: Article
Language:English
Subjects:
Animals
Epilepsy - etiology
Epilepsy - metabolism
Epilepsy - pathology
Female
Integrases - metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Neural Stem Cells - metabolism
Neurons - metabolism
Neurons - pathology
Neuroscience
Pyrophosphatases - physiology
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Summary: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 (Itpa-cKO 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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.140229