Abstract
The postsynaptic N-methyl-d-aspartate (NMDA) receptor activates multiple kinases and changes the phosphorylation of many postsynaptic proteins organized in signaling networks. Because the NMDA receptor is known to regulate gene expression, it is important to examine whether networks of kinases control signaling to gene expression. We examined the requirement of multiple kinases and NMDA receptor-interacting proteins for gene expression in mouse hippocampal slices. Protocols that induce long-term depression (LTD) and long-term potentiation (LTP) activated common kinases and overlapping gene expression profiles. Combinations of kinases were required for induction of each gene. Distinct combinations of kinases were required to up-regulate Arc, Npas4, Egr2, and Egr4 following either LTP or LTD protocols. Consistent with the combinatorial data, a mouse mutant model of the human cognition disease gene SAP102, which couples ERK kinase to the NMDA receptor, showed deregulated expression of specific genes. These data support a network model of postsynaptic integration where kinase signaling networks are recruited by differential synaptic activity and control both local synaptic events and activity-dependent gene expression.
Highlights
The process of learning involves the conversion of information within patterns of neuronal electrical activity into biochemical changes within neurons
A kinase network model would be an attractive mechanism for orchestrating the differential expression of genes and would be expected to be revealed by addressing the following questions: First, to what extent do multiple kinases regulate any given gene? Second, do stimulation paradigms that initiate long-term potentiation (LTP) and long-term depression (LTD) regulate common sets of genes? Third, are genes that are both regulated by LTP and LTD share the same dependence on specific kinases? Fourth, do mutations in NMDA receptor complex (NRC) proteins interfere with gene expression? To address these issues, we have studied NMDA receptor-activated gene expression in hippocampal slices from mice
We examined signaling from NMDA receptor to gene expression focusing on the differential roles played by multiple kinases in regulating downstream genes
Summary
The process of learning involves the conversion of information within patterns of neuronal electrical activity into biochemical changes within neurons. We have studied NMDA receptor-activated gene expression in hippocampal slices from mice. Inhibition of specific kinases shows that NMDA receptor activation of each gene is regulated by multiple kinases and that the set of kinases that regulates a gene may differ in LTP and LTD protocols.
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