20172
Cellular Phenotypes in Induced Pluripotent Stem Cells from Autistic Individuals

Friday, May 15, 2015: 10:55 AM
Grand Ballroom A (Grand America Hotel)
J. Price1, G. Cocks1, A. Kathuria2, K. Warre-Cornish1, R. Taylor3 and L. Andreae4, (1)Cells and Behaviour Unit, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom, (2)Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom, (3)MRC Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom, (4)MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom
Background:  The etiology of autism is poorly understood.  Genetic and environmental factors somehow converge during perinatal development to produce the combination of symptoms and co-morbidities that characterize this condition.  Induced pluripotent stem cells (iPSCs) permit not only the study of cellular phenotypes associated with autism, but also their developmental trajectory.  Thus this cellular system might offer a means to observe aspects of the etiology of autism in a simple in vitro model.

Objectives: To discover cellular phenotypes in iPSC-derived neurons associated with autism, and to observe their ontology

Methods: We generated iPSC lines from hair root biopsies from three categories of individuals: autistic patients carrying deletions in synaptic genes (SHANK3 and NRXN1); non-syndromic patients; and neurotypical control individuals.  We differentiated these iPSCs into parvocellular hypothalamic neurons, and devised cellular and molecular analyses to follow their differentiation.  

Results:   We discovered that cells from all three categories of individuals differentiate into parvocellular neuronal types as identified by RNASeq expression, electrophysiological recordings, and histochemical analyses, with GNrH+cells being the most numerous.  In neurons derived from the SHANK3 individuals, we see morphogenetic phenotypes: the cells develop a different size and shape from controls.   We also see differences in responsivity to cytokines that imply that the cells from autistic individuals carry epigenetic differences from controls.

Conclusions:  There are detectable cellular phenotypes observable in neurons derived from iPSCs that appear to be associated with autism.  This suggests that at least some of the pathophysiology associated with this condition can be captured in this cellular system.  What remains to be determined is how generalizable these phenotypes are across a range of autistic individuals, and the extent to which they correspond with clinical phenotypes, and with clinical heterogeneity.

See more of: EU-AIMS: Translating Cellular and Animal Models of Synaptic Gene Deficits to Large-Scale Clinical Studies
See more of: Brain Function (fMRI, fcMRI, MRS, EEG, ERP, MEG)