Neuroprotective role of dopamine against hippocampal cell death.
Glutamate excitotoxicity plays a key role in the induction of neuronal cell death occurring in many neuropathologies, including epilepsy. Systemic administration of the glutamatergic agonist kainic acid (KA) is a well characterized model to study epilepsy-induced brain damage. KA-evoked seizures in mice result in hippocampal cell death, with the exception of some strains that are resistant to KA excitotoxicity. Little is known about the factors that prevent epilepsy-related neurodegeneration. Here we show that dopamine has such a function through the activation of the D2 receptor (D2R). D2R gene inactivation confers susceptibility to KA excitotoxicity in two mouse strains known to be resistant to KA-induced neurodegeneration. D2R-/- mice develop seizures when administered KA doses that are not epileptogenic for wild-type (WT) littermates. The spatiotemporal pattern of c-fos and c-jun mRNA induction well correlates with the occurrence of seizures in D2R-/- mice. Moreover, KA-induced seizures result in extensive hippocampal cell death in D2R-/- but not WT mice. In KA-treated D2R-/- mice, hippocampal neurons die by apoptosis, as indicated by the presence of fragmented DNA and the induction of the proapoptotic protein BAX. These results reveal a central role of D2Rs in the inhibitory control of glutamate neurotransmission and excitotoxicity.
Bozzi
Y
Y
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, 67404 Illkirch Cedex, Communauté Urbaine de Strasbourg, France. yuri@in.pi.cnr.it
Vallone
D
D
Borrelli
E
E
D000818:Animals; D001345:Autoradiography; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D019262:Habenula / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D007178:Inbreeding; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics
D018696:Neuroprotective Agents; D017448:Receptors, Dopamine D2; D017470:Receptors, Glutamate; D007608:Kainic Acid; D004298:Dopamine