title: Transient muscarinic and glutamatergic stimulation of neural stem cells triggers acute and persistent changes in differentiation.
abstract: While aberrant cell proliferation and differentiation may contribute to epileptogenesis, the mechanisms linking an initial epileptic insult to subsequent changes in cell fate remain elusive. Using both mouse and human iPSC-derived neural progenitor/stem cells (NPSCs), we found that a combined transient muscarinic and mGluR1 stimulation inhibited overall neurogenesis but enhanced NPSC differentiation into immature GABAergic cells. If treated NPSCs were further passaged, they retained a nearly identical phenotype upon differentiation. A similar profusion of immature GABAergic cells was seen in rats with pilocarpine-induced chronic epilepsy. Furthermore, live cell imaging revealed abnormal de-synchrony of Ca(++) transients and altered gap junction intercellular communication following combined muscarinic/glutamatergic stimulation, which was associated with either acute site-specific dephosphorylation of connexin 43 or a long-term enhancement of its degradation. Therefore, epileptogenic stimuli can trigger acute and persistent changes in cell fate by altering distinct mechanisms that function to maintain appropriate intercellular communication between coupled NPSCs.
authors.affiliation: University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, USA; University of California Los Angeles, Department of Neurology, USA. Electronic address: ranmals@gmail.com.
authors.forename: Ranmal A
authors.initials: RA
authors.lastname: Samarasinghe
authors.affiliation: University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, USA.
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Kanuparthi
authors.affiliation: University of Pittsburgh School of Medicine-Pittsburgh, Institute of Neurodegenerative Diseases, USA.
authors.forename: J
authors.initials: J
authors.lastname: Timothy Greenamyre
authors.affiliation: University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, USA. Electronic address: dod1@pitt.edu.
authors.forename: Donald B
authors.initials: DB
authors.lastname: DeFranco
authors.affiliation: University of Pittsburgh School of Medicine-Pittsburgh, Institute of Neurodegenerative Diseases, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Maio
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004827:Epilepsy / Q000503:physiopathology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D010862:Pilocarpine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism
chemical_list: D018721:Muscarinic Agonists; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; C104077:metabotropic glutamate receptor type 1; D010862:Pilocarpine; D018698:Glutamic Acid
keywords: Connexin; Epileptogenesis; Glutamate receptor; Neural stem cell; Pilocarpine