Peer Reviewed


Document Type


Publication Date



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.

PubMed ID


DOI Link