Adaptor Proteins, Signal Transducing, Animals, Apoptosis, CA1 Region, Hippocampal, CA3 Region, Hippocampal, Glycogen Synthase Kinase 3, Kainic Acid, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphoproteins, Phosphorylation, Proto-Oncogene Proteins c-akt, Receptors, Dopamine D2, Seizures, Serine, Transcription, Genetic, Wnt Signaling Pathway, beta Catenin, p38 Mitogen-Activated Protein Kinases
Dopamine D2 receptor (D2R) signalling has been shown to modulate seizure-induced hippocampal cell death. D2R knockout (D2R-/-) mice are more susceptible to kainic acid (KA)-induced excitotoxicity, displaying cell death in the CA3 subfield of the hippocampus at KA doses not damaging in wild-type (WT) animals. Absence of D2R signalling in the hippocampus leads to activation (dephosphorylation) of glycogen synthase kinase 3β (GSK-3β) after KA (20 mg/kg), which is not associated with a change in the phosphorylation of the GSK-3β regulator Akt at the canonical threonine 308 residue. In the present study, we investigated alternative pathways responsible for the activation of GSK-3β in the hippocampus of the D2R-/- mice 24 h following KA-induced seizures. Here, we show that phosphorylation of Akt occurs at serine 473 (Ser473) in the CA3 region of WT but not D2R-/- mice following KA. Moreover, the CA1 subregion, which does not undergo neurodegeneration in either WT or D2R-/- mice, displays a strong induction of Akt (Ser473) phosphorylation after KA. Additionally, the vulnerability in the CA3 is not associated with changes to p38MAPK and Dishevelled activation, and β-catenin does not appear to be a downstream target of the GSK-3β. Thus, we propose that GSK-3β phosphorylation-mediated hippocampal cell survival may depend on Akt (Ser473) phosphorylation; loss of D2R-mediated signalling in the CA3 region of D2R-/- mice leads to reduced Akt (Ser473) phosphorylation rendering neurons more vulnerable to apoptosis. Further investigation is required to fully elucidate the GSK-3β targets involved in D2R-dependent response to excitotoxicity.
Physics | Physiology
Dunleavy M, Provenzano G, Henshall DC, Bozzi Y. Kainic acid-induced seizures modulate Akt (SER473) phosphorylation in the hippocampus of dopamine D2 receptor knockout mice. Journal of Molecular Neuroscience. 2013;49(1):202-10.