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The Journal of Neuroscience, July 16, 2003, 23(15):6304-6314
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Does cAMP Response Element-Binding Protein Have a Pivotal Role in Hippocampal Synaptic Plasticity and Hippocampus-Dependent Memory?
Detlef Balschun6,1 * David P. Wolfer,2 * Peter Gass,3,4 Theo Mantamadiotis,3,5 Hans Welzl,2 Günther Schütz,3 Julietta U. Frey,1 andHans-Peter Lipp2 1Department of Neurophysiology, Leibniz Institute for Neurobiology, 39108 Magdeburg, Germany, 2Institute of Anatomy and Center for Neuroscience, University of Zürich, 8057 Zürich, Switzerland, 3Department of Molecular Biology of the Cell I, German Cancer Research Center, University of Heidelberg, 69120 Heidelberg, Germany, 4Central Institute of Mental Health Mannheim, 68159 Mannheim, Germany, and 5Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, East Melbourne, 3002, Australia
Previous studies addressing the role of the transcription factor cAMP response element-binding protein (CREB) in mammalian long-term synaptic plasticity and memory by gene targeting were compromised by incomplete deletion of the CREB isoforms. Therefore, we generated conditional knock-out strains with a marked reduction or complete deletion of all CREB isoforms in the hippocampus. In these strains, no deficits could be detected in lasting forms of hippocampal long-term potentiation (LTP) and long-term depression (LTD). When tested for hippocampus-dependent learning, mutants showed normal context-dependent fear conditioning. Water maze learning was impaired during the early stages, but many mutants showed satisfactory scores in probe trials thought to measure hippocampus-dependent spatial memory. However, conditioned taste aversion learning, a putatively hippocampus-independent memory test, was markedly impaired. Our data indicate that in the adult mouse brain, loss of CREB neither prevents learning nor substantially affects performance in some hippocampus-dependent tasks. Furthermore, it spares LTP and LTD in paradigms that are sensitive enough to detect deficits in other mutants. This implies either a species-specific or regionally restricted role of CREB in the brain and/or a compensatory upregulation of the cAMP response element modulator (CREM) and other as yet unidentified transcription factors.
Key words: CREB; synaptic plasticity; LTP; LTD; learning; memory; water maze; fear conditioning; hippocampus; conditioned taste aversion
Received Dec. 16, 2002; revised Apr. 28, 2003; accepted May. 1, 2003.
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