Grant: Emerging Team Grant: From Genes to Proteins, Cells, Tissues and Patients - LOI

Schizophrenia and Autism Spectrum Disorders affect nearly 1% of the population, and both have strong developmental and genetic associations with 60-90% heritability among twins. Recent research identified genes that normally function to build synaptic connections between nerve cells to be altered in both autism and schizophrenia. Specifically, mutations in neuroligins have been linked to autism and mental retardation, and mutations in LRRTMs (as well as neuregulin, dysbindin, and DISC1) to schizophrenia. Mice engineered to bear autism-linked mutations in neuroligins exhibit impaired social interactions and have been developed as monogenic models for exploring and treating autism. At the cellular level, the function of neuroligins and LRRTMs to promote formation of functional synaptic connections between nerve cells is remarkably similar. Here, we propose to anlayze mice with mutations in LRRTMs, alone and in combination with mutations in neuroligins and DISC1. Assessment will include overall brain development; specificity, composition and function of nerve cell synaptic connections in development and in cellular models of learning; and behavioral assays for social interaction, depression, anxiety, and ability to appropriately filter sensorimotor information. At the same time, the genes encoding LRRTMs and other synaptogenic proteins will be sequenced in additional groups of patients with autism, schizophrenia, or mental retardation. Not only will this reveal the prevalence of disease-linked alterations in these genes, specific mutations sites will be mimicked in rodent models to understand how they alter function. It is our hope that the LRRTM mutant mice and ensuing multi-gene mouse models developed here will serve to better understand the molecular and cellular bases of these psychiatric disorders and thus to engineer rational therapies.