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

Abstract

Post-translational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, more than 150 human GPI anchored proteins have been discovered and about 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 (KA)-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.

Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice

“…Most of the ALS mice also evidenced an increase in spasticity by the retraction of the hindlimbs towards the abdomen and the closing of the fingers in a grasp, corresponding to the clasping and grasping reflexes, respectively. These disabilities associated with the corticospinal function might have been related to cerebellum dysfunction [ 82 , 83 ] and were observed previously in mSOD1 [ 41 ] and TDP-43 mouse models [ 84 , 85 ]. A less commonly used method, the cylinder test allowed us to evaluate the spontaneous activity and sensorimotor function of the mice, as described in [ 32 , 86 ].…”

Distal regulatory sequences contribute to diversity in brain oxytocin receptor expression patterns and social behavior

“…We systemically evaluated 8 founder lines by crossing them with ROSA-26-NLS- LacZ mice, a Cre reporter mouse line expressing nuclear-localized beta-galactosidase (21, 22). Since Lac-Z is only expressed in the nucleus of double positive (CRE+, LacZ+) cells but not in the neuronal processes, we could easily assess the expression pattern of our transgene.…”

“…We systemically evaluated 8 founder lines by crossing them with ROSA-26-NLS-LacZ mice, a Cre reporter mouse line expressing nuclear-localized beta-galactosidase (21,22).…”

Drosophilamodels of PIGA-CDG mirror patient phenotypes

“…While cell culture systems are useful for investigating the cellular effects of loss of PIGA, many effects are missed in cell models because there are many cell-type specific GPI anchored proteins. Mouse models have also been used to investigate PIGA-CDG (KAWAGOE et al 1996;LUKACS et al 2019;LUKACS et al 2020;KANDASAMY et al 2021;JANGID et al 2022). Global knockout of PIGA in mice is embryonic lethal (KAWAGOE et al 1996).…”