2013 Research Findings

The following studies were published in 2013. The grants awarded by ASF to fund these studies may have been distributed in years prior to 2013.

Phelan McDermid Syndrome Study

Using Induced-Pluripotent Stem Cells to Study Phelan McDermid Syndrome

Dr. Oleksandr Shcheglovitov

22q13.3 deletion syndrome (also known as Phelan-McDermid syndrome) is a genetic neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and autism. The syndrome is caused by the heterozygous microdeletions in the terminal region of chromosome 22. Although, a candidate gene responsible for the neurological abnormalities in patients has been suggested (SHANK3, which encodes a scaffolding protein of excitatory synapses), cellular and molecular defects associated with this syndrome were unknown. In the study published in the journal Nature, Dr. Oleksandr Shcheglovitov and a team of researchers from Stanford University reported that human neurons derived from induced pluripotent stem cells of patients with Phelan-McDermid syndrome and autism have deficits in excitatory synaptic transmission due to reduced number of excitatory synapses. The authors demonstrated that SHANK3 is primarily responsible for these deficits, as neurons from patients had reduced SHANK3 expression and increasing the levels of SHANK3 expression rescued synaptic deficits in patient cells.

The authors also tested several drugs for their ability to increase the number of excitatory synapses in neurons derived from patients and found that prolonged treatment with Insulin Growth Factor 1 (IGF1) completely restores excitatory synaptic transmission in patient cells. Interestingly, IGF1 produced its action by increasing the number of different type of excitatory synapses that express scaffolding protein PSD95 and lack SHANK3 expression.

In summary, this study brings important insights about the cellular and molecular mechanisms involved in the loss and gain of synaptic function in human neurons from patients with Phelan-McDermid syndrome and autism. It also provides encouragement that neurons derived from induced pluripotent stem cells of patients will be useful in understanding and developing treatments for neurodevelopmental and psychiatric disorders.

Read the full study here.

Behavioral Intervention Study

Correlation of cognitive and social outcomes among children with autism spectrum disorder in a randomized trial of behavioral intervention

Dr. Jill Locke

Although social impairments are considered the hallmark deficit of autism, many behavioral intervention studies rely on cognitive functioning as a primary outcome. Fewer studies have examined whether changes in cognition are associated with changes in social functioning. This study, led by Dr. Jill Locke and a team of researchers at the University of Pennsylvania, Temple University, and the University of Washington examined whether cognitive gains among 192 students from 47 kindergarten-through-second-grade autism support classrooms participating in a year-long behavioral intervention study were associated with gains in social functioning.

Children’s gains in cognitive ability were modestly associated with independent assessors’ and teachers’ evaluations of social functioning but were not associated with changes in parent ratings. Observed social gains were not commensurate with gains in cognition, suggesting the need both for interventions that directly target social functioning and relevant field measures of social functioning.

Read the full study here.

Rett Syndrome Study

Identifying genetic modifiers of Rett Syndrome in the mouse

Christie Buchovecky

Mutations in MECP2, encoding methyl CpG-binding protein 2, cause Rett syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2-null mice markedly improves function and longevity, providing hope that therapeutic intervention is possible in humans. Buchovecky and a team of other researchers isolated five suppressors that alleviate the symptoms of Mecp2 loss. They showed that a rate-limiting enzyme in cholesterol biosynthesis underlies suppression in one line. They also show that lipid metabolism is disturbed in the brains and livers of Mecp2-null male mice. Consistently, statin drugs, already being used by the public for treating high cholesterol, improve Rett Syndrome symptoms in Mecp2 mutant mice. This work therefore points to these cholesterol treatments as a potential target for the treatment of patients with Rett syndrome.

Read the full study here.

Infant Communication Study

Maternal verbal responses to communication of infants at low and heightened risk of autism

Nina Leezenbaum

In this study, Leezenbaum and other researchers investigated mothers’ responses to infant communication among infants at heightened genetic risk (high risk) of autism spectrum disorder compared to infants with no such risk (low risk). A total of 26 infants, 12 of whom had an older sibling with autism spectrum disorder, were observed during naturalistic in-home interaction and semistructured play with their mothers at 13 and 18 months of age. Results indicate that overall, mothers of low-risk and high-risk infants were highly and similarly responsive to their infants’ communicative behaviors. However, examination of infant vocal and gestural communication development together with maternal verbal responses and translations (i.e. verbally labeling a gesture referent) suggests that delays in early communication development observed among high-risk infants may alter the input that these infants receive; this in turn may have cascading effects on the subsequent development of communication and language.

Read the full study here.