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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-7 (01))
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Sieber, Beth-Anne
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University of Pittsburgh
Schools of Medicine
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Qiu, Shenfeng; Champagne, Danielle L; Peters, Melinda et al. (2010) Loss of limbic system-associated membrane protein leads to reduced hippocampal mineralocorticoid receptor expression, impaired synaptic plasticity, and spatial memory deficit. Biol Psychiatry 68:197-204
Koshibu, Kyoko; Levitt, Pat (2008) Gene x environment effects: stress and memory dysfunctions caused by stress and gonadal factor irregularities during puberty in control and TGF-alpha hypomorphic mice. Neuropsychopharmacology 33:557-65
Catania, Elizabeth Haldeman; Pimenta, Aurea; Levitt, Pat (2008) Genetic deletion of Lsamp causes exaggerated behavioral activation in novel environments. Behav Brain Res 188:380-90
Persico, Antonio M; Di Pino, Giovanni; Levitt, Pat (2006) Multiple receptors mediate the trophic effects of serotonin on ventroposterior thalamic neurons in vitro. Brain Res 1095:17-25
Koshibu, Kyoko; Levitt, Pat (2006) Transforming growth factor-alpha induces sex-specific neurochemical imbalance in the stress- and memory-associated brain structures. Neuropharmacology 50:807-13
Persico, A M; Levitt, P; Pimenta, A F (2006) Polymorphic GGC repeat differentially regulates human reelin gene expression levels. J Neural Transm 113:1373-82
Torii, Masaaki; Levitt, Pat (2005) Dissociation of corticothalamic and thalamocortical axon targeting by an EphA7-mediated mechanism. Neuron 48:563-75
Pimenta, Aurea F; Levitt, Pat (2005) Applications of gene targeting technology to mental retardation and developmental disability research. Ment Retard Dev Disabil Res Rev 11:295-302
Dennis, Kathleen E; Levitt, Pat (2005) Regional expression of brain derived neurotrophic factor (BDNF) is correlated with dynamic patterns of promoter methylation in the developing mouse forebrain. Brain Res Mol Brain Res 140:1-9
Koshibu, K; Levitt, P (2005) Sex differences in expression of transforming growth factor-alpha and epidermal growth factor receptor mRNA in Waved-1 and C57Bl6 mice. Neuroscience 134:877-87

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