Neural Stem Cell or Human Induced Pluripotent Stem Cell–Derived GABA‐ergic Progenitor Cell Grafting in an Animal Model of Chronic Temporal Lobe Epilepsy

Abstract

Grafting of neural stem cells (NSCs) or GABA-ergic progenitor cells (GPCs) into the hippocampus could offer an alternative therapy to hippocampal resection in patients with drug-resistant chronic epilepsy, which afflicts >30% of temporal lobe epilepsy (TLE) cases. Multipotent, self-renewing NSCs could be expanded from multiple regions of the developing and adult brain, human embryonic stem cells (hESCs), and human induced pluripotent stem cells (hiPSCs). On the other hand, GPCs could be generated from the medial and lateral ganglionic eminences of the embryonic brain and from hESCs and hiPSCs. To provide comprehensive methodologies involved in testing the efficacy of transplantation of NSCs and GPCs in a rat model of chronic TLE, NSCs derived from the rat medial ganglionic eminence (MGE) and MGE-like GPCs derived from hiPSCs are taken as examples in this unit. The topics comprise description of the required materials, reagents and equipment, methods for obtaining rat MGE-NSCs and hiPSC-derived MGE-like GPCs in culture, generation of chronically epileptic rats, intrahippocampal grafting procedure, post-grafting evaluation of the effects of grafts on spontaneous recurrent seizures and cognitive and mood impairments, analyses of the yield and the fate of graft-derived cells, and the effects of grafts on the host hippocampus.

Depression comorbidity in epileptic rats is related to brain glucose hypometabolism and hypersynchronicity in the metabolic network architecture

“…The forced swim test, described by Porsolt and colleagues is used to measure depressive behavior in animals. In this study, we used the protocol described previously . First, the animals were trained to swim for 10 minutes in a 45‐cm‐high cylinder filled with water at a temperature of 23‐25°C and a depth of 30 cm.…”

“…To analyze anhedonia, the sucrose preference test was used . On the first day, the animals were trained to adapt to sucrose solution for 24 hours.…”

“…This test examines the levels of depression and motivation to eat after food deprivation . In this test, all food was removed from the animal cages for 24 hours.…”

Models for discovery of targeted therapy in genetic epileptic encephalopathies

“…Similar information can also be obtained using transplantation of human stem cell‐derived neuronal precursor into the rodent brains (Imaizumi and Okano ; Upadhya et al . ), see further below. To conclude, generation of novel rodent models is not only valuable for our understanding of disease mechanisms but also critical for the development of novel therapies as these models present currently irreplaceable preclinical tools.…”

Progress in the molecular mechanisms of genetic epilepsies using patient‐induced pluripotent stem cells

“…Thus, iPSCs can provide a reliable platform for the study of the molecular mechanisms of GE. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Studies using iPSC technology to investigate the molecular mechanisms of GE have included studies focusing on Rett syndrome, Dravet syndrome, Phelan-McDermid syndrome (PMDS), and fragile X syndrome (FxS). Classic GE syndromes include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures alone (GTCS).…”