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J. Neurochem. (2011) 119, 447–459. Abstract Coffin–Lowry syndrome is a syndromic form of mental retardation caused by mutations of the Rps6ka3 gene encoding ribosomal s6 kinase (RSK)2. RSK2 belongs to a family containing four members in mammals: RSK1–4. RSKs are serine/threonine kinases and cytosolic substrates of extracellular signal-regulated kinase (ERK) in the Ras/MAPK signaling pathway. RSK2 is highly expressed in the hippocampus, and mrsk2_KO mice display spatial learning and memory impairment. In the present study, we provide evidence of abnormally increased phosphorylation of ERK1/2 in the hippocampus of mrsk2_KO mice. Further studies based on cultured hippocampal neurons revealed that glutamate activates ERK1/2 and RSKs, and confirmed a stronger activation of ERK1/2 in mrsk2_KO neurons than in WT cells. We, thus, provide further evidence that RSK2 exerts a feedback inhibitory effect on the ERK1/2 pathway. We also observed a transient sequestration of P-ERK1/2 in the cytoplasm upon glutamate stimulation. In addition, the transcription factors cAMP response element binding and Ets LiKe gene1 show over-activation in RSK2-deficient neurons. Finally, c-Fos, Zif268 and Arc were significantly over-expressed in mrsk2_KO neurons upon glutamate stimulation. Importantly, the increased phosphorylation of other RSK family members observed in mutant neurons was unable to compensate for RSK2 deficiency. This aberrant ERK1/2 signaling can influence various neuronal functions, and thus play a significant role in cognitive dysfunction in mrsk2_KO mice and in the Coffin-Lowry syndrome.

Coffin-Lowry syndrome is a syndromic form of mental retardation caused by mutations of the Rps6ka3 gene encoding ribosomal s6 kinase (RSK)2. RSK2 belongs to a family containing four members in mammals: RSK1-4. RSKs are serine/threonine kinases and cytosolic substrates of extracellular signal-regulated kinase (ERK) in the Ras/MAPK signaling pathway. RSK2 is highly expressed in the hippocampus, and mrsk2_KO mice display spatial learning and memory impairment. In the present study, we provide evidence of abnormally increased phosphorylation of ERK1/2 in the hippocampus of mrsk2_KO mice. Further studies based on cultured hippocampal neurons revealed that glutamate activates ERK1/2 and RSKs, and confirmed a stronger activation of ERK1/2 in mrsk2_KO neurons than in WT cells. We, thus, provide further evidence that RSK2 exerts a feedback inhibitory effect on the ERK1/2 pathway. We also observed a transient sequestration of P-ERK1/2 in the cytoplasm upon glutamate stimulation. In addition, the transcription factors cAMP response element binding and Ets LiKe gene1 show over-activation in RSK2-deficient neurons. Finally, c-Fos, Zif268 and Arc were significantly over-expressed in mrsk2_KO neurons upon glutamate stimulation. Importantly, the increased phosphorylation of other RSK family members observed in mutant neurons was unable to compensate for RSK2 deficiency. This aberrant ERK1/2 signaling can influence various neuronal functions, and thus play a significant role in cognitive dysfunction in mrsk2_KO mice and in the Coffin-Lowry syndrome.

International audience; The Coffin-Lowry syndrome, a rare syndromic form of X-linked mental retardation, is caused by loss-of-function mutations in the hRSK2 (RPS6KA3) gene. To further investigate RSK2 (90-kDa ribosomal S6 kinase) implication in cognitive processes, a mrsk2_KO mouse has previously been generated as an animal model of Coffin-Lowry syndrome. The aim of the present study was to identify possible neurochemical dysregulation associated with the behavioral and morphological abnormalities exhibited by mrsk2_KO mice. A cortical dopamine level increase was found in mrsk2_KO mice that was accompanied by an over-expression of dopamine receptor of type 2 and the dopamine transporter. We also detected an increase of total and phosphorylated extracellular regulated kinase that may be responsible for the increased level of tyrosine hydroxylase phosphorylation also observed. By taking into consideration previously reported data, our results strongly suggest that the dopaminergic dysregulation in mrsk2_KO mice may be caused, at least in part, by tyrosine hydroxylase hyperactivity. This cortical hyperdopaminergia may explain some non-cognitive but also cognitive alterations exhibited by mrsk2_KO mice.

Ribosomal S6 kinase2 (RSK2) is known to take part in several signal transduction cascades including Mitogen Activated Protein Kinase/Extracellular Regulated Kinase (MAPK/ERK). Following our recent observation that ERK can serve as a coincidence detector for fast and slow neurotransmission in the hippocampus, we analyzed the status of RSK2 phosphorylation subsequent to application of NMDA, dopamine, or both to preparations of mature hippocampal slices in Sprague-Dawley rats. RSK2 was indeed phosphorylated; however, in addition, the amount of RSK2 protein (60%) was induced within 10 min following stimulation. Moreover, the induced expression of RSK2 could be detected in both the cell body layer and the dendrites of hippocampal CA1 cells. Pharmacological analysis showed that RSK2 induction was MAPK ERK Kinase (MEK)-ERK independent, but mammalian Target of Rapamycin (mTOR) and translation dependent. We suggest that the fast kinetics of RSK2 translation that follows physiological stimulations, together with recent observations that its over-expression is vital for the attenuation of major signal transduction cascades, indicate an expanded physiological function of RSK2 in neurons, and sheds new light on the role of RSK2 in the Coffin-Lowry syndrome.