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.