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Experience recruits MSK1 to expand the dynamic range of synapses and enhance cognition

ABSTRACT: Experience powerfully influences neuronal function and cognitive performance, but the cellular and molecular events underlying the experience-dependent enhancement of mental ability have remained elusive. In particular, the mechanisms that couple the external environment to the genomic changes underpinning this improvement are unknown. To address this we have used male mice harbouring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a BDNF-activated enzyme downstream of the MAPK pathway. We show that MSK1 is required for the full extent of experience-induced improvement of spatial memory, for the expansion of the dynamic range of synapses, exemplified by the enhancement of hippocampal LTP and LTD, and for the regulation of the majority of genes influenced by enrichment. In addition, and unexpectedly, we show that experience is associated with an MSK1-dependent downregulation of key MAPK and plasticity-related genes, notably of EGR1/Zif268 and Arc/Arg3.1, suggesting the establishment of a novel genomic landscape adapted to experience. By coupling experience to homeostatic changes in gene expression MSK1, represents a prime mechanism through which the external environment has an enduring influence on gene expression, synaptic function and cognition.

ORGANISM(S): Mus musculus

PROVIDER: GSE149210 | GEO | 2020/05/10

REPOSITORIES: GEO

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Project description:Analysis of alterations in the hippocampus transcriptome caused by deletion of Mitogen Stress activated Kinase 1 (MSK1). MAPK signaling has been implicated in a wide range of neuronal processes, including development, plasticity and viability. One of the principal downstream targets of both the ERK/MAPK pathway and the p38 MAPK pathway is Mitogen Stress activated Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized a MSK1 null mouse line, cell viability assays and array-based profiling approaches. Here we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus (SE) drives acute induction of MSK1 activation. In response to the SE paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of NMDA-evoked excitotoxicity relative to WT neurons, as assessed using the LDH assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that with MSK1 deletion a total of 115 genes showed significant changes (> 1.25-fold) in expression. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults. MAPK signaling has been implicated in a wide range of neuronal processes, including development, plasticity and viability. One of the principal downstream targets of both the ERK/MAPK pathway and the p38 MAPK pathway is Mitogen Stress activated Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized a MSK1 null mouse line, cell viability assays and array-based profiling approaches. Here we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus (SE) drives acute induction of MSK1 activation. In response to the SE paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of NMDA-evoked excitotoxicity relative to WT neurons, as assessed using the LDH assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that with MSK1 deletion a total of 115 genes showed significant changes (> 1.25-fold) in expression. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults.

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Experience recruits MSK1 to expand the dynamic range of synapses and enhance cognition

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