Abnormal development of neuronal circuitry is thought to underlie the characteristic behavioral manifestations of autism spectrum disorder (ASD) and related disorders like Rett syndrome. The aberrant size and function of specific brain regions that has been documented in ASD is likely to result from aberrant development of neurons and synapses, features that can be quantified using in vitro approaches. This application proposes to develop an inexpensive, cell-based assay of neuronal morphogenesis and synaptogenesis that will facilitate both basic research and pre-clinical drug development for ASD. The morphology-based assay will be amenable to automated, high-content screening of neurons derived from either animal models or from induced pluripotent stem cells (iPS cells) from human patients with ASD and related disorders. Neurite outgrowth, dendritic branching, spine shape, and synaptic markers will be quantified. Proof of concept experiments will be conducted to evaluate differences in neuronal development in iPS cells (supplied by collaborator) from Rett syndrome patients compared to unaffected individuals.
This pilot project will develop quantitative, microscopy-based assays of neuronal development that can be used to evaluate neurons derived from lines of induced pluripotent stem cells of patients with autism and related disorders. The assay will facilitate a) the assessment of heterogeneity in neuronal development among patient populations and across individuals with autistic syndromes;b) investigation of molecular mechanisms underlying abnormal neuronal development;and c) screening of pharmaceutical compounds that may improve normal neuronal development in autism.
| Dehmelt, Leif; Poplawski, Gunnar; Hwang, Eric et al. (2011) NeuriteQuant: an open source toolkit for high content screens of neuronal morphogenesis. BMC Neurosci 12:100 |
