The long-term goals of this project are to define the mechanisms that regulate the assembly of brain regions and circuits that are involved in mediating emotion, cognition, memory and learning. The applicant has focused his efforts on the development of the cerebral cortex, which has been implicated in neurodevelopmental alterations that underlie certain neuropsychiatric disorders, including schizophrenia. During the past grant period, we defined: 1) the intrinsic and environmental signals that control expression of regional phenotypes in limbic and neocortical areas and 2) the molecules that may control axon guidance and target recognition between limbic and non-limbic areas of the forebrain. Key molecules include the limbic system-associated membrane protein (Lamp), whose gene we recently cloned, neurotrimmin (Ntm), a related Ig superfamily member and Ephrin-A5, a ligand that activates the eph receptor Eph-A5. Each molecule has complex biological activities, exhibiting both attractive and repulsive cues for different populations of limbic and non-limbic neurons. Dual activity is consistent with our anatomical analysis showing that Lamp expression patterns in the cortex and thalamus are complementary to Ntm and Ephrin-A5. We have proposed four specific aims to assess directly the role of Lamp and Ephrin-A5 and Ntm in the guidance and targeting of subsets of limbic and non-limbic axons in the thalamocortical system. Production of animals that have a targeted deletion of Lamp will be completed and animals expressing compound mutations of Lamp and Ephrin-A5 will be produced. The consequences of these genetic mutations will be determined by analyzing developing and thalamocortical and cortico-cortical axon organization and targeting. The domains of Lamp that mediate growth-enhancing and repulsive/inhibitory activity will be determined in cellular assays using mutant, recombinant forms of the protein. The principal investigator will use homologous recombination at the emx-1 locus to determine the developmental consequences of mis- or overexpression of Lamp specifically throughout the cerebral cortex. Examination of intrinsic and environmental factors that regulate anatomically specific expression patterns of Ephrin-A5 and Ntm will be done using in vitro assays as in previous studies of Lamp. The proposed experiments are designed to use molecular genetic, anatomical, and cell-biological strategies to address fundamental problems related to axon guidance and circuit formation in the developing limbic system.
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