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 adm inistration of the glutamatergic agonist kainic acid (KA) is a well charact erized model to study epilepsy-induced brain damage. KA-evoked seizures in mice result in hippocampal cell death, with the exception of some strains t hat are resistant to KA excitotoxicity. Little is known about the factors t hat prevent epilepsy-related neurodegeneration. Here we show that dopamine has such a function through the activation of the D2 receptor (D2R). D2R ge ne inactivation confers susceptibility to KA excitotoxicity in two mouse st rains known to be resistant to KA-induced neurodegeneration. D2R-/- mice de velop seizures when administered KA doses that are not epileptogenic for wi ld-type (WT) littermates. The spatiotemporal pattern of c-fos and c-jun mRN A induction well correlates with the occurrence of seizures in D2R-/- mice. Moreover, KA-induced seizures result in extensive hippocampal cell death i n D2R-/- but not WT mice. In KA-treated D2R-/- mice, hippocampal neurons di e by apoptosis, as indicated by the presence of fragmented DNA and the indu ction of the proapoptotic protein BAX. These results reveal a central role of D2Rs in the inhibitory control of glutamate neurotransmission and excito toxicity.