Gene by Environment Influences on Forebrain Development

University Of Southern California, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): Early disruptions in neuronal development due to genetic and environmental factors (G x E) together contribute to whether a neurodevelopmental disorder will be expressed and the severity of symptoms. These interactions underlie autism spectrum disorders (ASD), which is characterized by deficits in social communication and repetitive behaviors that can be highly heterogeneous, even for ASDs with known genetic causes. To date, much of the research has focused on defining genetic contributions to ASD risk, but there is a significant gap in knowledge between the growing understanding of the role of genetic mechanisms governing brain development and the lack of understanding of environmental contributions to pathophysiology in neurodevelopmental disorders. The laboratory discovered a functional promoter allele in the gene encoding the human MET receptor tyrosine kinase, an ASD risk allele that reduces transcription and protein expression by ~50%. Genetically deleting Met in mice leads to changes in neuronal structure and connectivity in the mouse forebrain. Homozygous or heterozygous Met mice exhibit altered interlaminar excitatory drive and certain behaviors. Early life stress is a major factor that can lead to disrupted brain development and risk for, or exacerbation of neurodevelopmental disorders. Developmental G x E models incorporate the introduction of early adversity that targets specific circuitry. Here, the experimental design includes an early-life stressor that targets MET-positive circuits mediating emotional and social behavior. I hypothesize that early-life stress interacts during development with genetic risk that causes disrupted MET expression, which results in the development of atypical neuronal and synaptic maturation, and ultimately behavior. Specific Aim 1 will determine the effect of early-life stress in Met heterozygous mice on mRNA, protein expression and signaling by MET and its ligand, hepatocyte growth factor (HGF) in the hippocampus and frontal cortex. Changes in microRNAs that are stress-responsive and also regulate Met and Hgf expression will be measured. Specific Aim 2 will use intracellular dye labeling and three-dimensional morphometric analyses to determine the impact of the combined challenge on the architecture of pyramidal neurons in MET-positive CA1 hippocampal and infralimbic medial prefrontal cortex neurons. Accompanying expression changes of pre- and postsynaptic proteins that are altered in Met null mice will be determined in the Met+/- mice exposed to early-life stress. The impact of G x E on contextual fear learning, which is impaired in Met+/- mice, also will be measured. The results of these studies will provide novel insight into the interaction between well-delineated genetic and environmental factors, and their combined impact on neuronal maturation relevant to complex brain functions.