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Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP

Abstract

Cyclic AMP is a positive regulator of synaptic plasticity and is required for several forms of hippocampus-dependent memory including recognition memory. The type I adenylyl cyclase, Adcy1 (also known as AC1), is crucial in memory formation because it couples Ca2+ to cyclic AMP increases in the hippocampus. Because Adcy1 is neurospecific, it is a potential pharmacological target for increasing cAMP specifically in the brain and for improving memory. We have generated transgenic mice that overexpress Adcy1 in the forebrain using the Camk2a (also known as α-CaMKII) promoter. These mice showed elevated long-term potentiation (LTP), increased memory for object recognition and slower rates of extinction for contextual memory. The increase in recognition memory and lower rates of contextual memory extinction may be due to enhanced extracellular signal–related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling, which is elevated in mice that overexpress Adcy1.

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Figure 1: FLAG-Adcy1 retains Ca2+-stimulated adenylyl cyclase activity.
Figure 2: Region-specific expression of FLAG-Adcy1 in mouse brain.
Figure 3: Overexpression of Adcy1 does not affect the morphology of the hippocampus.
Figure 4: Enhancement of CA1 LTP in transgenic mice.
Figure 5: Mice that overexpress Adcy1 have enhanced memory for object recognition and elevated amounts of pErk1/2 and pCREB.
Figure 6: Adcy1-overexpressing mice show normal memory for contextual and cued learning.
Figure 7: Adcy1-overexpressing mice have higher amounts of pErk1/2 and pCREB after contextual training and slower extinction of contextual memory.

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Acknowledgements

We thank members of the Storm laboratory for suggestions and critical reading of the manuscript. The Camk2a promoter was from M. Mayford. This research was supported by the National Institutes of Health (NS 20498 to D.R.S., AG 00057 to H.W. and Public Health Service National Research Service Award 1F31NS042475-01 to V.V.P.).

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Correspondence to Daniel R Storm.

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Wang, H., Ferguson, G., Pineda, V. et al. Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nat Neurosci 7, 635–642 (2004). https://doi.org/10.1038/nn1248

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