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. We have focused our efforts on establishing evidence that functional disruption of molecules involved in the formation of limbic circuits can lead to neurodevelopmental alterations that may be related to human psychopathologies. Experimental studies in vitro have implicated the limbic system-associated membrane protein (LAMP) in circuit development. LAMP is a member of the IgLON subfamily of cell adhesion molecules that participate in axon guidance and plasticity. During the past grant period, we utilized in vitro assays and molecular manipulations to further investigate LAMP function as an axon guidance cue and gene targeting strategies to create Lamp null mice for neurodevelopmental, molecular and functional analyses. Related to the current proposal, we found that 1) genetic disruption of Lamp expression causes developmental alterations of a specific limbic circuit, 2) adult Lamp-/- mice exhibit abnormal behavior on tests of anxiety and stress, and 3) limbic brain regions in the Lamp -/- mice undergo compensatory changes in gene expression. In the current proposal, we have integrated complementary methodologies in developmental neuroanatomy, behavior, proteomics and genomics to address four specific aims: 1) Experiments in Lamp -/- and +/+ mice will assess directly the role of LAMP in the formation and maintenance of forebrain limbic circuits using dye labeling, intercrossed YFP- expressing mice and retrograde tracing. 2) Tasks that test anxiety, stress response and memory will be used to develop a more complete understanding of how loss of LAMP impacts complex behavioral and cognitive functions. 3) Protein-protein interactions that mediate LAMP function and changes in gene expression that occur following loss of Lamp will be examined. We will use proteomics to identify inter- and intracellular partners that are involved in LAMP function during axon guidance and in the adult. We will use genomic methods to define the (mal) adaptive changes caused by genetic deletion of Lamp. 4) A gene targeting strategy with a transactivator rescue system will be used to temporally and spatially regulate the expression of Lamp in the forebrain. We will utilize this model to identify distinct pleiotropic functions of LAMP. Together, the proposed studies have broad relevance for understanding morphological, molecular and cell signaling changes that underlie neuropsychiatric disorders characterized by altered limbic system development and function. ? ?
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