Excitatory tonus is required for the survival of granule cell precursors during postnatal development within the cerebellum.

Autor: Kanungo AK; Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 3M2., Liadis N, Robertson J, Woo M, Henderson JT
Jazyk: angličtina
Zdroj: Neuroscience [Neuroscience] 2009 Feb 18; Vol. 158 (4), pp. 1364-77. Date of Electronic Publication: 2008 Nov 08.
DOI: 10.1016/j.neuroscience.2008.10.062
Abstrakt: 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.
Databáze: MEDLINE
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