The cbl-b gene is a member of the cbl protooncogene family. It encodes a protein with multiple domains, which can interact with other proteins in a variety of signaling pathways. The functions of cbl family genes in the brain are unknown. In this report, we used genetic, immunohistochemical, behavioral, and electrophysiological approaches to study the role of cbl-b in learning and memory. Cbl-b null mice developed normally and had no abnormalities in their locomotor performance. In spatial learning and memory studies, cbl-b null and WT mice performed similarly during training. To test memory retention, two probe trials were used. cbl-b null mice performed slightly better 1 day after training. However, in the probe trial 45 days after training, the cbl-b null group showed significantly higher memory retention than WT mice, suggesting an enhancement of long-term memory. Using electrophysiological approaches, we found there was enhanced paired-pulse facilitation in the Schaffer Collateral-CA1 glutamatergic synapses of the cbl-b null mice. On the other hand, there was no difference in long-term potentiation between the two groups of mice. In summary, we provide evidence that (i) cbl-b protein is concentrated in the synaptic regions of CA1, CA3, and the dentate gyrus of the hippocampus; (ii) cbl-b null mice have enhanced long-term memory; and (iii) cbl-b null mice show an enhancement in short-term plasticity. These results indicate that cbl-b is a negative regulator of long-term memory, and its neuronal mechanism regulates synaptic transmission in the hippocampus.cbl-b knockout mice ͉ hippocampus ͉ paired-pulse facilitation W ith the human and mouse genomes fully sequenced, many candidate genes that may be related to the process of learning and memory are available for gene targeting and other mutagenesis studies. Analysis of the behavioral, physiological, and biochemical consequences of these mutations will help implicate molecular pathways important for learning and memory, as well as their underlying synaptic mechanisms.Cbl-b belongs to the cbl-protooncogene family. It contains multiple functional domains, including a tyrosine kinase-binding (TKB) domain, a RING-finger domain, and a proline-rich region, as well as an ubiquitin-associated domain. The TKB domain has been shown to recognize specific phosphotyrosine residues on activated tyrosine kinases (1, 2). The RING-finger domain is the site whereby cbl family proteins recruit ubiquitinconjugating enzymes, which add ubiquitin to targeted proteins. These domains are required for cbl family proteins to regulate signaling transduction and protein degradation. C-cbl and cbl-b genes are strongly expressed in thymus, testes, and other tissues (3). Gene targeting in mice has shown that cbl-b is involved in pivotal events of lymphocyte activation (4, 5).Although earlier Northern hybridization demonstrated that cbl-b mRNAs are expressed in many tissues, including the brain (3), the distribution of the cbl-b protein and its function in the brain are still unknown.To unders...