There is considerable evidence that the interaction between genetic susceptibly and environmental (GxE) risk factors plays a significant role in neuropsychiatric disease. In particular, GxE interactions are exemplified by attention-deficit hyperactivity disorder (ADHD) and schizophrenia that are prominent heterogeneous mental illnesses, with ADHD affecting 5-8% of school-aged children and schizophrenia having a life-long prevalence of 0.5-1%. While several genetic loci have been implicated in the heritability of these disorders, and environmental factors have been identified from population-based studies, there are few animal models that have been developed to examine the impact of GxE effects to study the mechanism of these interactions. In this application, we address this important goal by exploiting the hypothesis that the convergence of genetically encoded deficits in SNAP-25 expression, resulting selective deficiencies in synaptic transmission, and the environmental impact of prenatal nicotine exposure during brain development leads to emergent alterations of synaptic plasticity in the striatum. The potential involvement of the neural SNARE protein SNAP-25 as a candidate gene for neuropsychiatric disease has been revealed in our early studies of the hyperactive mouse mutant coloboma, more recently by genetic linkage studies in the ADHD population and by number of biochemical analyses schizophrenia. Similarly, maternal smoking is associated with increased incidence of ADHD. Towards this goal, we propose two Specific Aims in an R21 proposal that we believe may have high impact in the field by developing this model of GxE that can be evaluated mechanistically by targeting the genetic lesion to different neural systems and by receptor signaling assays that are contribute to synaptic plasticity in the striatum. Our strategy is to develop an innovative, integrated approach that capitalizes on the molecular genetic, neuropharmacological and electrophysiological expertise of our laboratories.
The Specific Aims are: 1) to evaluate mechanism of GxE effects on synaptic plasticity (long-term depression, LTD) through dopamine D2 receptor signaling and expression and 2) to identify those components of striatal circuitry responsible for deficits in synaptic plasticity by targeting haploinsufficiency of the Snap25 gene to specific inputs to the striatum. Ultimately, we expect that this strategy could be adopted and expanded to define the significant contributions of GxE factors to alterations in gene expression and epigenetic regulation, and the deficits in synaptic plasticity and cognitive behaviors that are the cornerstones of mental illness. Furthermore we believe that this research will aid in the development of better, more targeted therapeutics tuned at a systems level to the neurophysiological basis of neuropsychiatric disorders.
Many prominent neuropsychiatric disorders, such as attention-deficit hyperactivity disorder (ADHD) and schizophrenia, show a clear pattern of inheritance, as well as a striking role for environmental risk factors. Despite this clear evidence for the role of genes x environment interactions, the lack of well-defined animal models has limited our ability to understand the fundamental basis of how these factors interact to promote different clinical presentations of neuropsychiatric disease. Our investigation of a mouse model based on SNAP25 as susceptibility gene and prenatal nicotine exposure would not only help resolve the neurophysiological mechanisms involved, but importantly should aid in the development of better targeted therapeutics based on the brain circuitry revealed by these studies.
| Baca, Michael; Allan, Andrea M; Partridge, L Donald et al. (2013) Gene-environment interactions affect long-term depression (LTD) through changes in dopamine receptor affinity in Snap25 deficient mice. Brain Res 1532:85-98 |
| Blakey, Daniel; Wilson, Michael C; Molnár, Zoltán (2012) Termination and initial branch formation of SNAP-25-deficient thalamocortical fibres in heterochronic organotypic co-cultures. Eur J Neurosci 35:1586-94 |
