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The molecular and cellular biology of enhanced cognition

Key Points

  • Although there is considerable evidence for animals and people with cognitive enhancements, mechanistic studies of enhanced cognition are comparatively rare.

  • Genetic manipulations of more than 30 different genes have been shown to enhance learning and memory (L&M) in mutant mice. These 'smart' mice provide powerful tools to investigate the cellular and molecular mechanisms underlying L&M enhancements.

  • Strikingly, long-term potentiation (LTP) is enhanced in most of the mutant mice with enhanced L&M, providing a compelling argument for a role of LTP-like mechanisms in L&M.

  • It is possible to enhance synaptic plasticity and L&M by manipulating various neuronal signalling molecules, ranging from membrane receptors to nuclear transcription factors. Interestingly, N-methyl-D-aspartate (NMDA) receptor signalling and subsequent cyclic-AMP response-element-binding protein (CREB)-dependent transcription are upregulated in many mutant mice with enhanced L&M.

  • Targeting the molecular mechanisms that are associated with L&M enhancements may lead to the development of general therapies for cognitive disorders, and could represent a novel strategy to address the extraordinary complexity of the genetic and environmental factors responsible for the myriad of cognitive disorders that affect a surprisingly large percentage of the population.

Abstract

Most molecular and cellular studies of cognitive function have focused on either normal or pathological states, but recent research with transgenic mice has started to address the mechanisms of enhanced cognition. These results point to key synaptic and nuclear signalling events that can be manipulated to facilitate the induction or increase the stability of synaptic plasticity, and therefore enhance the acquisition or retention of information. Here, we review these surprising findings and explore their implications to both mechanisms of learning and memory and to ongoing efforts to develop treatments for cognitive disorders. These findings represent the beginning of a fundamental new approach in the study of enhanced cognition.

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Figure 1: NMDAR-dependent signalling and downstream kinases and phosphatases implicated in learning and memory enhancement.
Figure 2: Regulation of CREB-dependent gene expression involved in memory formation.
Figure 3: Integrating pathways for learning and memory enhancement.

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Acknowledgements

We would like to thank members of the Silva laboratory for discussions that shaped this Review. We would like to give B. Dobkin a special thanks for his enthusiasm for this project, the Adelson Foundation, Korea Research Foundation (KRF-2007-357-C00101), NIA (AG13622), NINDS (NS38480) and NIMH (MH077972) for funding that made this work possible.

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Rubinstein-Taybe syndrome

Rubinstein-Taybe syndrome is a genetic disorder that occurs in 1/125,000 births and is characterized by mental retardation, broad thumbs and toes, and facial abnormalities. It can be caused by heterozygous mutations in CREB binding protein (CBP).

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Lee, YS., Silva, A. The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 10, 126–140 (2009). https://doi.org/10.1038/nrn2572

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