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The Journal of Neuroscience, June 7, 2006, 26(23):6230-6237; doi:10.1523/JNEUROSCI.1182-06.2006

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Behavioral/Systems/Cognitive
Environmental Enrichment Enhances Neurogranin Expression and Hippocampal Learning and Memory But Fails to Rescue the Impairments of Neurogranin Null Mutant Mice

Freesia L. Huang, Kuo-Ping Huang, Junfang Wu, and Catherine Boucheron

Section on Metabolic Regulation, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510

Correspondence should be addressed to Freesia Huang, 49 Convent Drive, MSC 4510, National Institutes of Health, Bethesda, MD 20892. Email: fhuang{at}mail.nih.gov

Environmental enrichment is known to enhance hippocampal neurogenesis and cognitive functions. Neurogranin (Ng), a specific substrate of protein kinase C (PKC), is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng in mice causes severe deficits in spatial learning and long-term potentiation (LTP) in the hippocampal CA1 region. These Ng–/– mice, as compared with Ng+/+, respond poorly after treatment of their hippocampal slices with agents that activate signaling molecules important for learning and memory, including Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), PKC, protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). In the present study, adult mice were housed in either regular home cages (control group) or more spacious cages with an exercise wheel and change of toys twice per week (enriched group) for at least 3 weeks. Enriched Ng+/+ and Ng+/– mice showed enhanced LTP in the hippocampal CA1 after high-frequency stimulation, but Ng–/– mice were affected only minimally. Behaviorally, the enriched Ng+/+ and Ng+/–, but not Ng–/– mice, performed significantly better than their respective control cohorts in Morris water maze and in step-down fear conditioning. Enriched Ng+/– mice also showed improvement in the radial arm maze. Quantitative immunoblot analyses showed that the enriched groups of all three genotypes exhibited elevated hippocampal levels of CaMKII and CREB, but not ERK. Interestingly, enrichment caused a significant increase in hippocampal Ng levels both in Ng+/+ and Ng+/– mice that seemed to contribute to their improved LTP and behavioral performances. These results suggest that Ng gates the neuronal signaling reactions involved in learning and memory. During environmental enrichment, these Ng-regulated reactions are also critical for the enhancement of synaptic plasticity and cognitive functions.

Key words: neurogranin; environmental enrichment; Ca²⁺/calmodulin; learning and memory; synaptic plasticity; hippocampus

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Received March 18, 2006; revised April 29, 2006; accepted April 30, 2006.

Correspondence should be addressed to Freesia Huang, 49 Convent Drive, MSC 4510, National Institutes of Health, Bethesda, MD 20892. Email: fhuang{at}mail.nih.gov

This article has been cited by other articles:

				P. K. Shetty, F. L. Huang, and K.-P. Huang Ischemia-elicited Oxidative Modulation of Ca2+/Calmodulin-dependent Protein Kinase II J. Biol. Chem., February 29, 2008; 283(9): 5389 - 5401. [Abstract] [Full Text] [PDF]

				F. L. Huang, K.-P. Huang, and C. Boucheron Long-term enrichment enhances the cognitive behavior of the aging neurogranin null mice without affecting their hippocampal LTP Learn. Mem., August 1, 2007; 14(8): 512 - 519. [Abstract] [Full Text] [PDF]

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