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The Journal of Neuroscience, November 15, 2000, 20(22):8643-8649
Neuroprotective Role of Dopamine Against Hippocampal Cell
Death
Yuri
Bozzi,
Daniela
Vallone, and
Emiliana
Borrelli
Institut de Génétique et de Biologie Moléculaire
et Cellulaire, Centre National de la Recherche Scientifique/Institut
National de la Santé et de la Recherche
Médicale/Université Louis Pasteur, 67404 Illkirch Cedex,
Communauté Urbaine de Strasbourg, France
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.
Key words:
epilepsy; excitotoxicity; apoptosis; dopamine D2
receptors; glutamate receptors; kainic acid
Copyright © 2000 Society for Neuroscience 0270-6474/00/20228643-07$05.00/0
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