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.

Aldose reductase (ALR2) is thought to be involved in the pathogenesis of various diseases associated with diabetes mellitus, such as cataract, retinopathy, neuropathy, and nephropathy. However, its physiological functions are not well understood. We developed mice deficient in this enzyme and found that they had no apparent developmental or reproductive abnormality except that they drank and urinated significantly more than their wild-type littermates. These ALR2-deficient mice exhibited a partially defective urine-concentrating ability, having a phenotype resembling that of nephrogenic diabetes insipidus.Aldose reductase (ALR2) is the first enzyme in the polyol pathway. It was first described by Hers in 1956 (13). Using NADPH as a cofactor, it reduces glucose to sorbitol in addition to reducing other sugars to their respective polyols. The activation of the sorbitol pathway under hyperglycemic conditions is thought to be the cause of diabetic lesions in tissues where the import of glucose is independent of insulin, such as the lens, vascular cells, and nervous tissues (18,28). Although ALR2 has been thoroughly studied for its role in the etiology of diabetic complications, its physiological functions are not well understood. ALR2 is present in most tissues surveyed and has been implicated in a wide variety of physiological functions. It is thought to be responsible for synthesizing fructose in the seminal vesicle to be used as the main energy source for sperm motility, because fructose is converted from sorbitol by the enzyme sorbitol dehydrogenase (SORD) (13). ALR2 can efficiently reduce methyglyoxal (35), 4-hydroxynonenal (34), and 3-deoxyglucosone (29), suggesting that it may be responsible for detoxification of these and other harmful metabolites. Another postulated function of ALR2 is osmoprotection in the kidney (1). This is based on the facts that sorbitol is an inert compound ideally suited as an osmolyte and that its intracellular concentration in certain tissues can reach a high enough level to affect osmotic pressure. Further, elevated extracellular NaCl was shown to elicit a marked increase in ALR2 expression and the accumulation of intracellular sorbitol in the cell line cultured from rabbit renal medullae (1), suggesting that kidney cells respond to an increase in extracellular osmotic pressure by producing more sorbitol. In support of this notion, osmotic response elements have been identified in the promoter regions of the rabbit (10) and human (20) ALR2 genes.To test these proposed functions of ALR2, we developed two mouse lines deficient in this enzyme. ALR2 knockout mice (Aldor1 Ϫ/Ϫ ) appeared to grow normally and did not show any obvious abnormalities in their reproductive function. Upon closer examination, they were found to have developed polyuria and polydipsia. These Aldor1 Ϫ/Ϫ mice exhibit a partially defective urine-concentrating ability, leading to a phenotype resembling that of diabetes insipidus (DI).There are several known causes of DI. Deficiency in the synthesis or secretion of t...

L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation and axon outgrowth and guidance. Mutations in the human and mouse L1 gene result in similarly severe neurological abnormalities. To dissociate the functional roles of L1 in the adult brain from developmental abnormalities, we have generated a mutant in which the L1 gene is inactivated by cre-recombinase under the control of the calcium/calmodulin-dependent kinase II promoter. This mutant (L1fy+) did not show the overt morphological and behavioral abnormalities observed previously in constitutive L1-deficient (L1-/-) mice; however, there was an increase in basal excitatory synaptic transmission that was not apparent in L1-/- mice. Similar to L1-/- mice, no defects in short- and long-term potentiation in the CA1 region of the hippocampus were observed. Interestingly, L1fy+ mice showed decreased anxiety in the open field and elevated plus-maze, contrary to L1-/- mice, and altered place learning in the water maze, similar to L1-/- mice. Thus, mice conditionally deficient in L1 expression in the adult brain share some abnormalities, but also display different ones, as compared with L1-/- mice, highlighting the role of L1 in the regulation of synaptic transmission and behavior in adulthood.