RRC ID 61621
Author Koga Y, Tsuchimoto D, Hayashi Y, Abolhassani N, Yoneshima Y, Sakumi K, Nakanishi H, Toyokuni S, Nakabeppu Y.
Title Neural stem cell-specific ITPA deficiency causes neural depolarization and epilepsy.
Journal JCI Insight
Abstract 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.
Volume 5(22)
Published 2020-11-19
DOI 10.1172/jci.insight.140229
PII 140229
PMID 33208550
PMC PMC7710303
MeSH 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* Pyrophosphatases / physiology*
IF 6.205
Mice RBRC01834