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Genetic enhancement of learning and memory in mice

Abstract

Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic coincidence detection would lead to better learning and memory. If the NMDA (N-methyl-D-aspartate) receptor, a synaptic coincidence detector1,2,3,4, acts as a graded switch for memory formation, enhanced signal detection by NMDA receptors should enhance learning and memory. Here we show that overexpression of NMDA receptor 2B (NR2B) in the forebrains of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10–100 Hz. These mice exhibit superior ability in learning and memory in various behavioural tasks, showing that NR2B is critical in gating the age-dependent threshold for plasticity and memory formation. NMDA-receptor-dependent modifications of synaptic efficacy, therefore, represent a unifying mechanism for associative learning and memory. Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.

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Figure 1: Construction and biochemical characterization of transgenic NR2B mice.
Figure 2: Developmental changes in NMDA current at single synapse.
Figure 3: Selective enhancement of 10–100-Hz-induced potentiation in transgenic mice.
Figure 4: Enhanced novel-object recognition memory in transgenic mice.
Figure 5: Enhancement of both contextual and cued fear memory in transgenic mice.
Figure 6: Transgenic mice exhibit faster learning in fear extinction.
Figure 7: Enhanced performance in the hidden-platform water maze task by transgenic mice.

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Acknowledgements

We thank G. Bracket and L. Antonucci and their staff for the maintenance of Princeton Mouse Facility, M. Mayford and E. Kandel for providing the CaMKII promoter, S. Tonegwa for support of J.R.T.'s early cloning work (1995) on plasmid p279NB from which pJT-NR2B is derived and D. Prout for secretarial assistance and proofreading. This work was supported by Princeton University, Beckman Foundation and NIH (J.Z.T.).

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Correspondence to Joe Z. Tsien.

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Tang, YP., Shimizu, E., Dube, G. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999). https://doi.org/10.1038/43432

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