The MAPK/ERK Cascade Targets Both Elk-1 and cAMP Response Element-Binding Protein to Control Long-Term Potentiation-Dependent Gene Expression in the Dentate Gyrus In Vivo

By S. Davis, P. Vanhoutte, C. Pagès, J. Caboche, S. Laroche. Journal of Neuroscience, 2000

654 citations recorded by the source corpus.

The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade contributes to synaptic plasticity and to long-term memory formation, yet whether MAPK/ERK controls activity-dependent gene expression critical for long-lasting changes at the synapse and what the events underlying transduction of the signal are remain uncertain. Here we show that induction of long-term potentiation (LTP) in the dentate gyrus in vivo leads to rapid phosphorylation and nuclear translocation of MAPK/ERK. Following a similar time course, the two downstream transcriptional targets of MAPK/ERK, cAMP response element-binding protein (CREB) and the ternary complex factor Elk-1, a key transcriptional-regulator of serum response element (SRE)-driven gene expression, were hyperphosphorylated and the immediate early gene zif268 was upregulated. The mRNA encoding MAP kinase phosphatase MKP-1 was upregulated at the time point when MAPK/ERK phosphorylation had returned to basal levels, suggesting a negative feedback loop to regulate deactivation of MAPK/ERK. We also show that inhibition of the MAPK/ERK cascade by the MAPK kinase MEK inhibitor SL327 prevented CREB and Elk-1 phosphorylation, and LTP-dependent gene induction, resulting in rapidly decaying LTP. In conclusion, we suggest that Elk-1 forms an important link in the MAP kinase pathway to transduce signals from the cell surface to the nucleus to activate the genetic machinery necessary for the maintenance of synaptic plasticity in the dentate gyrus. Thus, MAPK/ERK activation is required for LTP-dependent transcriptional regulation and we suggest this is regulated by two parallel signaling pathways, the MAPK/ERK-Elk-1 pathway targeting SRE and the MAPK/ERK-CREB pathway targeting CRE.

Subfields: Cellular and Molecular Neuroscience, Complementary and alternative medicine, Neurology

View Paper: https://www.semanticscholar.org/paper/a230bebcee1df74ca06e8e3ab3d02aa774a1e527

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. E. Bruel-Jungerman
2. S. Laroche
3. Richard L. Huganir
4. C. Bramham
5. M. Lynch
6. C. Rampon
7. T. Bliss
8. S. Waddell

In Complementary and alternative medicine

1. T. Bliss

In Neurology

1. E. Bruel-Jungerman
2. S. Davis
3. C. Rampon
4. S. Laroche
5. Richard L. Huganir
6. C. Bramham
7. M. Lynch
8. T. Bliss

Citations in the corpus

• Brain-Derived Neurotrophic Factor Induces Long-Term Potentiation in Intact Adult Hippocampus: Requirement for ERK Activation Coupled to CREB and Upregulation of Arc Synthesis (2002, background): “ERK and CREB have emerged as critical points of convergence in the signaling pathways regulating gene transcription in late LTP and long-term memory (Atkins et al., 1998; Impey et al., 1998; Davis et al., 2000).”
• MAPK cascade signalling and synaptic plasticity (2004, background): “Following LTP-inducing stimuli, phospho-ERK immunoreactivity develops rapidly in both dendritic and somatic regions of hippocampal neuron”
• Long-term potentiation and memory. (2004, background): “CaMKII Increased CaMKII phosphorylation of synapsin I (175, 449) and MAP2 (175) with LTP CaMK inhibitors block LTP (369, 373) Injection of Ca(2) -independent CaMKII blocks LTP (220, 337, 494) Injection of constitutively active CaMKII induces LTP (337, 494) cAMP LTP activates PKA presynaptically (615”
• Long-Term Potentiation Enhances Neurogenesis in the Adult Dentate Gyrus (2006, methodology): “We induced LTP in the DG unilaterally, each rat serving as its own control, using surgical and LTP-inducing procedures described previously (Davis et al., 2000).”