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PMID:11069974
| Citation |
Bozzi, Y, Vallone, D and Borrelli, E (2000) Neuroprotective role of dopamine against hippocampal cell death. J. Neurosci. 20:8643-9 |
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| Abstract |
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. |
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| Keywords |
Animals; Autoradiography; Cell Death/drug effects; Cell Death/physiology; Dopamine/metabolism; Dopamine/pharmacology; Dose-Response Relationship, Drug; Female; Habenula/metabolism; Habenula/pathology; Heterozygote; Hippocampus/drug effects; Hippocampus/metabolism; Hippocampus/pathology; Homozygote; In Situ Nick-End Labeling; Inbreeding; Kainic Acid/pharmacology; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Neuroprotective Agents/metabolism; Neuroprotective Agents/pharmacology; Receptors, Dopamine D2/metabolism; Receptors, Glutamate/metabolism; Seizures/chemically induced; Seizures/genetics |
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Significance
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