Genes and signaling pathways involved in memory enhancement in mutant mice

Abstract

Mutant mice have been used successfully as a tool for investigating the mechanisms of memory at multiple levels, from genes to behavior. In most cases, manipulating a gene expressed in the brain impairs cognitive functions such as memory and their underlying cellular mechanisms, including synaptic plasticity. However, a remarkable number of mutations have been shown to enhance memory in mice. Understanding how to improve a system provides valuable insights into how the system works under normal conditions, because this involves understanding what the crucial components are. Therefore, more can be learned about the basic mechanisms of memory by studying mutant mice with enhanced memory. This review will summarize the genes and signaling pathways that are altered in the mutants with enhanced memory, as well as their roles in synaptic plasticity. Finally, I will discuss how knowledge of memory-enhancing mechanisms could be used to develop treatments for cognitive disorders associated with impaired plasticity.

Figure 1

Molecules involved in memory enhancement. Signaling pathways in the presynaptic axonal terminal and the postsynaptic dendritic spine and nucleus are illustrated in a simplified manner. Green and red arrows indicate positive and negative regulations, respectively. Memory is enhanced either by the over expression/activation of molecules colored in green or the deletion/inhibition of molecules in red. The detailed roles of some of these molecules in LTP and memory are described in the text. Cbl-b, casitas B-lineage lymphoma-b; NCX2, Na⁺/Ca²⁺ exchanger type 2; GAP-43, growth-associated protein 43; tPA, tissue-type plasminogen activator; HB-GAM, heparin-binding growth-associated molecule; MMP-9, Matrix metallopeptidase 9; GABA, γ-aminobutyric acid; MAGL, Monoacylglycerol lipase; CaMKII, calcium calmodulin kinase II; BDNF, Brain-derived neurotrophic factor; Cdk5, Cyclin-dependent kinase 5; Cavβ3, beta intracellular subunit of the voltage-gated calcium channel; PKA, protein kinase A; PDE, phosphodiesterase; PP1, protein phosphatase 1; MAPK, mitogen-activated protein kinase; CaMKIV, calcium calmodulin kinase IV; CN, calcineurin; ATF4, activating transcription factor 4; GCN2, general control nonderepressible 2; p-eIF2α, phosphorylated eukaryotic translation initiation factor 2 subunit α.