Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models

Lenin C Kandasamy; Mina Tsukamoto; Vitaliy Banov; Sambuu Tsetsegee; Yutaro Nagasawa; Mitsuhiro Kato; Naomichi Matsumoto; Junji Takeda; Shigeyoshi Itohara; Sonoko Ogawa; Larry J Young; Qi Zhang

doi:10.1093/hmg/ddab052

Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models

Hum Mol Genet. 2021 May 28;30(9):758-770. doi: 10.1093/hmg/ddab052.

Authors

Lenin C Kandasamy¹, Mina Tsukamoto¹, Vitaliy Banov^{2

3}, Sambuu Tsetsegee¹, Yutaro Nagasawa¹, Mitsuhiro Kato⁴, Naomichi Matsumoto⁵, Junji Takeda⁶, Shigeyoshi Itohara², Sonoko Ogawa⁷, Larry J Young^{8

9}, Qi Zhang^{1

2

8}

Affiliations

¹ Laboratory of Social Neural Networks, Center for Social Neural Networks, University of Tsukuba, Tsukuba 305-8577, Japan.
² Laboratory for Behavioral Genetics, CBS, RIKEN, Wako 351-0198, Japan.
³ Institute of Neuroinformatics, University of Zürich, ETH Zürich, Zürich 8057, Switzerland.
⁴ Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8555, Japan.
⁵ Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
⁶ Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
⁷ Laboratory of Behavioral Neuroendocrinology, Faculty of Human Sciences, University of Tsukuba, Tsukuba 305-8577, Japan.
⁸ Faculty of Human Sciences, Center for Social Neural Networks, University of Tsukuba, Tsukuba 305-8577, Japan.
⁹ Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta GA 30329, USA.

Abstract

Posttranslational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, >150 human GPI-anchored proteins have been discovered and ~30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian GPI. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder. We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko) or thalamic neurons (Th-H-cko), respectively. Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid-induced seizures. In addition, In-M-cko demonstrated a severe limb-clasping phenotype. Hippocampal synapse changes were observed in Ex-M-cko mice. Our Piga conditional knockout mouse models provide powerful tools to understand the cell-type specific mechanisms underlying inherited GPI deficiency and to test different therapeutic modalities.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cognition
Glycosylphosphatidylinositols* / deficiency
Humans
Kainic Acid* / metabolism
Mammals
Mice
Mice, Knockout
Mutation
Neurons / metabolism
Seizures / genetics
Seizures / metabolism

Substances

Glycosylphosphatidylinositols
Kainic Acid

Supplementary concepts

Glycosylphosphatidylinositol deficiency