Michael E. Coulter - US grants

DESCRIPTION (provided by applicant): Intellectual disabilities (ID) and autism spectrum disorders (ASD) are highly prevalent disorders of developmental delay with substantial overlap. ID and ASD are highly heritable, but because of genetic heterogeneity only about 15% of ASD patients and 50% of ID patients have a specific genetic diagnosis. Identified genetic causes of ASD and ID suggest common genetic pathways in disease pathogenesis including synaptic dysfunction, cytoskeletal dynamics in spine development, the Ras-MAPK pathway, and histone modification. In collaboration with two fellows in the laboratory of my sponsor, Christopher A. Walsh, I have recently identified a large family from the Kingdom of Saudi Arabia and the United Arab Emirates with recessively inherited ID with autistic features. We have identified a truncating mutation in a novel, uncharacterized gene in all affected individuals from this family. An unanswered question in developmental neurobiology is how the various cellular pathways that contain identified ASD and ID genes are coordinated in normal cognitive development. Understanding the function of this gene, a predicted methyltransferase that may regulate multiple genes through protein modification, can provide insight into coordination between cellular pathways for cognitive development disrupted in ASD and ID. I propose the following experiments to investigate the function of this gene. In Specific Aim 1, I will determine if the truncating mutation in this family is a loss of function allele, and will search for additional loss of function alleles in this gene in other ID and ASD patients. In Specific Aim 2, I will characterize subcellular localization, interaction partners, and methyltransferase activity of the protein encoded by this gene. In Specific Aim 3, I will collaborate with the lab of my co-sponsor, Michael Greenberg, to characterize neuron morphology and activity-dependent gene expression in the absence of this gene.

PROJECT SUMMARY / ABSTRACT Memory is an integral component of human cognition, and when memory processes go awry, the result is devastating neurological disorders of memory loss including Alzheimer's disease and other forms of dementia. One essential role of normal memory processes is to use previous experience to guide decisions about future actions. Thus, research to define the neural mechanisms of memory processes is important to understand both normal brain function and what goes wrong in memory loss disorders. Further, insights from these studies could help develop new treatments for these disorders. Recent work showed that synchronized neuron firing events in the hippocampus called sharp wave ripples (SWRs) that occur during awake immobility are required for rapid learning during spatial memory tasks. SWRs often contain specific place-cell firing sequences that closely resemble firing during prior experiences (?replay? events), suggesting a potential neural mechanism for retrieval of specific prior experiences. However, not all awake SWRs contain replay events that encode experiences related to the current environment, and so whether the specific content of replay is required for learning remains an unanswered question. I hypothesize that content-specific replay events serve to retrieve specific prior experiences and so are required for learning and decision-making. To date, this hypothesis has not been directly tested and the lack of tests is a major gap in our understanding of neural mechanisms of memory processes. In preliminary work, I have developed a system that decodes and classifies replay events in real-time and can provide behavioral or neural feedback based on the content of a replay event. I will use this system to test three related hypotheses, (1) replay content can be modulated by behavioral conditioning, (2) specific replay content can drive behavior, and (3) specific replay content is required for learning. In addition to these experiments, my fellowship training plan includes research and academic goals. My research goals are to investigate fundamental neural mechanisms of memory processes and to learn the methods of in vivo physiology and computational neuroscience. My academic goals are to build a strong foundation in computational neuroscience and continue to improve the career development skills I will need for my transition to independence at the end of this fellowship. Together, the labs of my sponsor, Loren Frank, and co-sponsor, Uri Eden, and the UCSF scientific community will provide an excellent training environment. Dr. Frank is a leading expert in the field of chronic hippocampal recording and neural data analysis methods. Dr. Eden is an expert in methods of computational and theoretical neuroscience, including the algorithms I will use in my experiments. UCSF is a premier academic research institution for medicine and neurobiology with a strong focus on collaboration and plentiful career development resources for postdoctoral fellows.