Mental retardation is caused by a variety of factors including mutations that affect brain development and therefore impair cognitive function. However, some of the genes involved in brain development may also have roles in the adult CNS. Disruption of these adult functions could result in learning deficits independently of any developmental abnormalities. Importantly, these post-development impairments in function may be more easily reversible than changes established during development. For example, previous studies involved the Notch pathway in neurogenesis. Additionally, recent findings demonstrated the expression of Notch 1 in the post-natal brain suggesting that this pathway may also have a role in modulating function in the adult brain. Additionally, recent findings demonstrated the expression of Notch 1 in the post-natal brain suggesting that this pathway also have a role in modulating function in the adult brain. Interestingly, our laboratory found that Notch 1 heterozygous mice (Notch+/-) have specific spatial learning and memory deficits, while motor coordination and other behaviors required to test spatial learning seemed unaffected by this mutation. Since Notch 1 is expressed in the adult hippocampus, we propose to study the impact of the Notch+/- mutation in hippocampal physiology and in other hippocampal-dependent learning and memory. To determine whether disruption of the Notch pathway specifically in adult neurons can affect cognitive function, we will take advantage of the LBD-inducible strategy that we recently used successfully to regulate the transcription factor CREB in adult mice. We will manipulate Notch function by fusing the RBP-J(R218H) dominant-negative gene with a mutant estrogen receptor ligand-binding domain (LBD/G521R). Injection of tamoxifen (the inducer) should trigger the activation of the Notch 1 dominant-negative repressor. We will use both types of mutant mice to address the following questions: 1- Is the Notch pathway required for learning and memory? Is it required for any other behaviors? 2- Is the Notch pathway required for hippocampal synaptic function?
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