The most significant advances in ASD research using iPSCs have been obtained from studies on patients with Rett Syndrome, an Autism Spectrum Disorder that affects approximately 1 in 10,000 girls. Most cases with Rett Syndrome result from mutations in the MECP2 gene; the MeCP2 protein encoded by this gene regulates the expression of a wide range of genes in neurons and other cells. A 2010 publication demonstrated that neurons derived from patients with Rett syndrome had smaller cell bodies than neurons derived from healthy controls¹.

Furthermore, this study also demonstrated that Rett syndrome neurons had fewer synapses, exhibited altered calcium signaling, and showed a decreased frequency of spontaneous postsynaptic currents than control neurons. This publication also demonstrated the potential utilization of iPSC-derived neurons in the screening of drugs to potentially treat ASD. Treatment of Rett syndrome neurons with the drug IGF1 led to an increase in the number of synapses, while treatment with the antibiotic gentamicin led to increased expression of MeCP2 protein and consequently an increased number of synapses. Subsequent publications have also demonstrated smaller neuronal size and defects in neuronal maturation in neurons derived from Rett syndrome patients^2-4.

References
1. Marchetto MCN, et al. (2010) A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143: 527-539. PMID: 21074045.

2. Cheung AYL, et al. (2011) Isolation of MECP2-null Rett syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum. Mol. Genet. 20(11): 2103-2115. PMID: 21372149.

3. Kim K-Y, et al. (2011) Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc. Natl. Acad. Sci. U.S.A. 108(34): 14169-14174. PMID: 21807996.

4. Ananiev G, et al. (2011) Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS One 6(9): e25255. PMID: 21966470.

Timothy syndrome is a multiorgan disorder caused by a point mutation in the CACNA1C gene, which encodes for a calcium channel subunit. In addition to cardiac arrhythmia and hypoglycemia, a significant number of Timothy syndrome patients also exhibit ASD. In a 2011 publication, researchers demonstrated that neurons derived from iPSCs from Timothy syndrome patients showed defects in calcium signaling, gene expression, and differentiation¹. This study also demonstrated that one of the phenotypes observed in Timothy syndrome neurons—increased production of the neurotransmitters norepinephrine and dopamine—could be reversed by treating cells with the calcium channel blocker roscovitine.

References
1. Paşca SP, et al. (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17(12): 1657-1662. PMID: 22120178.

Fragile X syndrome, one of the most common causes of intellectual disability, typically results from expansion of a CGG trinucleotide repeat in the FMR1 gene. This in turn leads to the loss of expression of the Fragile X Mental Retardation protein FMRP. A subset of Fragile X patients also develops ASD. Neurons derived from patients with Fragile X syndrome displayed fewer and shorter processes than control neurons¹.  In a recent publication, iPSC-derived neurons were generated from fibroblasts of a female carrier such that neurons either contained the normal version of the FMR1 gene or the expanded form of the FMR1 gene.  Neurons containing the expanded version of the FMR1 gene showed altered synapses, reduced neurite length, and abnormal calcium signalling compared to neurons with the normal version of the FMR1 gene².

References
1. Sheridan SD, et al. (2011) Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of Fragile X syndrome. PLoS One 6(10): e26203. PMID: 2202256

2. Liu J, et al. (2012) Signaling defects in iPSC-derived fragile X premutation neurons.  Hum. Mol. Genet. (Epub ahead of print).  PMID: 22641815

While classical Rett syndrome results from mutations in the MECP2 gene, several atypical forms of the syndrome also exist.  One of these forms, known as the Hanefeld variant, is caused by mutations in the X-linked CDKL5 gene.  In a recent report, iPSC-derived neurons were generated from the fibroblasts of two female patients diagnosed with atypical Rett syndrome resulting from CDKL5 mutations. The neurons from these patients exhibited no changes in neuronal differentiation or morphology, but they did display a reduced number of synaptic contacts and abnormal spine structure¹.

 

References

1. Ricciardi S, et al. (2012) CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons.  Nature Cell Biol.  PMID:  22922712.

References
1. DeRosa BA, et al. (2012) Derivation of autism spectrum disorder-specific induced pluripotent stem cells from peripheral blood mononuclear cells. Neurosci. Lett. Epub ahead of print. PMID: 22405972.