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 calciumcalmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMffϩ) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAMϪ/Ϫ) mice. However, similar to the NCAMϪ/Ϫ mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMffϩ mice. The deficit in LTP could be rescued by elevation of extracellular Ca 2ϩ concentrations from 1.5 or 2.0 to 2.5 mM, suggesting an involvement of NCAM in regulation of Ca 2ϩ -dependent signaling during LTP. Contrary to the NCAMϪ/Ϫ mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMffϩ as opposed to abnormal lamination in NCAMϪ/Ϫ mice. NCAMffϩ 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 NCAMϪ/Ϫ mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.
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