SFARI | Search Results for “ben-ari”

Role of Ube3a in neocortical plasticity and function

Angelman syndrome is a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, seizures and the absence of speech, and it shows a high comorbidity with autism. The syndrome is caused by maternal deletion or mutation of a single gene that encodes the ubiquitin protein ligase E3A (UBE3A). The paternal copy of UBE3A is silenced in neurons, and therefore the loss of maternal UBE3A results in a complete absence of the protein in most areas of the brain. UBE3A is an enzyme that targets proteins for degradation, a process that maintains normal functioning within cells.

Assembly of cortical microcircuit motifs in a mouse model of Arid1b haploinsufficiency

Understanding how ASD risk genes alter the course of cortical circuit development is necessary to advance targeted therapies. In the current project, Jason Wester plans to investigate how Arid1b mutations in different types of neurons within the mouse cerebral cortex leads to pathological circuit configurations that disrupt information processing.

Fever, meningeal immunity and immune factors in autism

Fever or fever-associated illness in children with autism is reported to result in temporary relief of cognitive and behavioral symptoms. It remains unknown, however, which aspects of this phenomenon — such as temperature increase, immune activation, type of pathogen or type of autism — are important for this benefit to occur.

Elucidating pathogenic mutations disrupting RNA regulation in autism

Efforts to find genetic causes of autism have identified hundreds of rare mutations in individuals with the disorder, and this list is anticipated to grow steadily in the next few years. A pressing question is which of the mutations are responsible for conferring a disease risk. A small number of the mutations appear likely to disrupt the function of the affected genes, and individuals with autism have a higher burden of these mutations, suggesting a causative link to the disorder. However, the majority of mutations change only a single amino acid of the protein product or are ‘silent’ according to the genetic code. These mutations occur at similar frequencies in individuals with autism and unaffected siblings, implying that most of them are probably benign.

Efficacy of N-acetyl cysteine in autism

There is an immense need to find new treatments for children with autism. While some current therapies are effective, there is a lack of treatments that have a clear scientific basis. There is significant evidence to show that children with autism have decreased antioxidant defenses. This may lead to changes in the way cells function and contribute to the symptoms that children experience.

Cellular and circuit effects of SCN2A haploinsufficiency

Dysfunction in SCN2A, which encodes the neuronal sodium channel NaV1.2, is strongly linked to autism spectrum disorder (ASD). Building on the recent finding that multiple ASD-associated mutations in SCN2A dampen or eliminate NaV1.2 channel function, the Bender Lab is now exploring how loss of SCN2A function affects developing and mature neuronal networks in mouse models.

CRISPR activation-based approach to rescue cellular and behavioral deficits associated with Scn2a haploinsufficiency

Kevin Bender and Nadav Ahituv aim to determine whether upregulation of the remaining functional allele with CRISPR activation-based techniques can rescue cellular and behavioral deficits observed in Scn2a heterozygous mice. If successful, this approach may be applicable to other haploinsufficient genes associated with autism spectrum disorders.

Comprehensive follow-up of novel autism genetic discoveries

Based on a genome-wide association study, Mark Daly of Massachusetts General Hospital and his colleagues reported in 2008 that genetic variation in the 16p11.2 chromosomal region is a major risk factor for autism. Daly and colleagues also uncovered more than 100 other rare genetic variations that appear to contribute to risk of autism, but these polymorphisms need further confirmation to prove an association with the disorder. Taking advantage of the SFARI Simplex Collection, the researchers plan to intensively sequence the implicated regions to find rare point mutations that would not be detectable using past or current genome scanning techniques.

Understanding the cellular and circuit bases for behavioral impairments in the Scn2a knock-out rat

Tremendous strides have been made in determining the genetic basis of ASD, but we continue to struggle to understand the links from genes to cells to circuits to behavior. Loren Frank, Kevin Bender and David Kastner plan to study a rat model of ASD, Scn2a haploinsufficiency, at the cellular, systems and behavioral levels in an effort to understand how genetically driven changes in cellular properties drive systems-level changes in activity patterns and behavioral changes in the ability to learn and to adapt to new situations.

High-throughput drug discovery in zebrafish models of autism risk genes

One of the most critical challenges in the identification of new medications to treat autism spectrum disorders (ASDs) is our limited understanding of the biological mechanisms underlying these disorders. In recent years, there have been considerable advances in the genetics of ASD, with a resulting rapidly accumulating pool of reliable ASD risk genes. Currently, we need systems that will allow us to progress from gene discovery to the illumination of relevant biological pathways and novel therapeutics.