title: Excitatory tonus is required for the survival of granule cell precursors during postnatal development within the cerebellum.
abstract: In addition to protective effects within the adult central nervous system (CNS), in vivo application of N-methyl-d-aspartate inhibitors such as (+) MK-801 have been shown to induce neurodegeneration in neonatal rats over a specific developmental period. We have systematically mapped the nature and extent of MK-801-induced neurodegeneration throughout the neonatal murine brain in order to genetically dissect the mechanism of these effects. Highest levels of MK-801-induced neurodegeneration are seen in the cerebellar external germinal layer; while mature neurons of the internal granule layer are unaffected by MK-801 treatment. Examination of external germinal layer neurons by electron microscopy, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and bromodeoxyuridine (BrdU) labeling, and caspase-3 activation demonstrate that these neurons die through the process of programmed cell death soon after they exit from the cell cycle. Significantly, ablation of caspase-3 activity completely inhibited the MK-801-induced (and developmental) programmed cell death of external germinal layer neurons. Similar to caspase-3, inactivation of muscarinic acetylcholine receptors in vivo using scopolamine inhibited MK-801-induced programmed cell death. By contrast, the GABAergic agonist diazepam, either alone or in combination with MK-801, enhanced programmed cell death within external germinal layer neurons. These data demonstrate that, in vivo, cerebellar granule neurons undergo a dramatic change in intracellular signaling in response to molecules present in the local cellular milieu during their first 24 h following exit from the cell cycle.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 3M2.
authors.forename: A K
authors.initials: AK
authors.lastname: Kanungo
authors.forename: N
authors.initials: N
authors.lastname: Liadis
authors.forename: J
authors.initials: J
authors.lastname: Robertson
authors.forename: M
authors.initials: M
authors.lastname: Woo
authors.forename: J T
authors.initials: JT
authors.lastname: Henderson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3 / Q000172:deficiency / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D012601:Scopolamine / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*
chemical_list: D018680:Cholinergic Antagonists; D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D016291:Dizocilpine Maleate; D012601:Scopolamine; D053148:Caspase 3; D001973:Bromodeoxyuridine; D003975:Diazepam