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The Journal of Neuroscience, February 18, 2004, 24(7):1565-1577; doi:10.1523/JNEUROSCI.3298-03.2004
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Development/Plasticity/Repair
Conditional Ablation of the Neural Cell Adhesion Molecule Reduces Precision of Spatial Learning, Long-Term Potentiation, and Depression in the CA1 Subfield of Mouse Hippocampus
Olena Bukalo,1 * Nikolas Fentrop,1 * Alan Y. W. Lee,1 * Benedikt Salmen,1 * Janice W. S. Law,1 Carsten T. Wotjak,1,2 Michaela Schweizer,1 Alexander Dityatev,1 andMelitta Schachner1 1Zentrum fuer Molekulare Neurobiologie, Universitaet Hamburg, D-20246 Hamburg, Germany, and 2Max-Planck-Institut fuer Psychiatrie, D-80804 Munich, Germany
NCAM, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation, axon outgrowth and fasciculation, and synaptic plasticity. To dissociate the functional roles of NCAM in the adult brain from developmental abnormalities, we generated a mutant in which the NCAM gene is inactivated by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMff+) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAM-/-) mice. However, similar to the NCAM-/- mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMff+ mice. The deficit in LTP could be rescued by elevation of extracellular Ca2+ concentrations from 1.5 or 2.0 to 2.5 mM, suggesting an involvement of NCAM in regulation of Ca2+-dependent signaling during LTP. Contrary to the NCAM-/- mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMff+ as opposed to abnormal lamination in NCAM-/- mice. NCAMff+ mutants did not show general deficits in short- and long-term memory in global landmark navigation in the water maze but were delayed in the acquisition of precise spatial orientation, a deficit that could be overcome by training. Thus, mice conditionally deficient in hippocampal NCAM expression in the adult share certain abnormalities characteristic of NCAM-/- mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.
Key words: CA1; hippocampus; long-term depression; long-term potentiation; NCAM; water maze
Received July 11, 2003; revised December 10, 2003; accepted December 12, 2003.
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