Dissecting Non-coding RNA Function in Critical Period Brain Development/ Disorder

It is generally accepted that normal function in the nervous system depends on the correct pattern of connections between neurons and their targets. Plasticity is the neuronal property that creates and consolidates new connections. Much of our adult behavior reflects the neural circuits sculpted by experience in infancy and early childhood. It is likely that defects in synaptic rearrangement that are manifest during such critical periods are a major cause of many developmental disorders of behavior like autism, schizophrenia and ADHD. This project explores the mechanisms underlying critical periods of brain development. Research is aimed at the interface between cell biology and neuroscience - applying cellular/molecular techniques to elucidate complex neural systems. By focusing on GABA circuits, Dr. Hensch has achieved the first direct control over critical period timing in any system. Understanding how plasticity waxes and wanes with age carries an impact far beyond neuroscience, including education policy, therapeutic approaches to developmental disorders or strategies for recovery from brain injury in adulthood. In this project he will examine the role of non-coding RNAs in this vital process. The hypothesis is that specific ncRNAs act as molecular switches to regulate gene networks within neural networks. To achieve cell-specificity, a technique of magnetofection to target cell types at their time and place of origin will be developed. Using replication-defective adenoviral vectors coupled to magnetic beads, successful “pulse gene transfer” can be performed into progenitor cells in a neuronal birthdate-specific manner. His strategy therefore involves the cell-specific deletion of enzymes that generate micro or short ncRNAs. Specific ncRNAs can further be disrupted at precise promoter sequences by peptide nucleic acids. The goal is to observe which ncRNAs need to be functional in which cell types to ensure a healthy activity-dependent brain development, and conversely which disruptions mimic human developmental disorders such as autism.

Period of Support: 9/30/07 - 7/31/12