Genetic studies have provided compelling evidence that heritable factors play a prominent role in the risk for developing a number of major mental disorders including schizophrenia, bipolar disorder and Alzheimer's disease. Furthermore, neurobiologic studies have demonstrated structural, metabolic and synaptic neurochemical abnormalities in individuals affected with these major mental disorders. A critical issue, at this juncture, is how the gap between molecular genetics and neurobiology might be bridged to begin to understand the mechanisms whereby abnormal gene expression affects brain development and function. As a clinically relevant and heuristically useful strategy, this Neuroscience Work Group will focus on the neurobiologic consequences of gene imbalance of mouse chromosome 16 (MMU16). Previous studies of this Group and of others have demonstrated extensive homology between a portion of MMU16 and human chromosome 21 (HSA 21). Down Syndrome (DS) results from triplication of the distal end of the long arm of HSA 21. DS is the most common genetically identified cause of mental retardation, is associated with a high risk for affective disorder, and invariably results in the pathology of Alzheimer's disease by the fourth decade. Mice with trisomy of MMU16 (Ts16) can be generated reproducibly by a specific breeding scheme. These mice exhibit many of the phenotypic characteristics of DS, including endocardial cushion defects, brain hypoplasia, synaptic neurochemical abnormalities and altered expression of amyloid precursor protein (APP). The Group, which has collaborated effectively for seven years, includes members with expertise in molecular genetics, developmental neurobiology, synaptic neurochemistry, and physiologic psychology. In the proposed studies, the Group will utilize mice with Ts16 and exploit current molecular strategies to generate mice transgenic for specific genes on MMU16 to determine how perturbation of the copy numbers of specific genes or group of genes affects their expression in the developing nervous system. Specifically, in Project I, mice will be developed that are transgenic for specific genes or portions thereof; such mice are directly relevant to the experimental goals of the other three projects. Project II will utilize both Ts16 mice and mice with specific transgenes to determine intrinsic and extrinsic fetal brain cells to identify factors that impair basal forebrain cholinergic development, somatostatin expression, and sensitivity to oxidative stress in Ts16, features analogous to those observed in DS.
