SFARI

Seizures are an extreme outcome of excitatory-inhibitory imbalance and are the most common neurological complication in autism spectrum disorder (ASD). Seizures are even more common in syndromic forms of ASD such as Angelman syndrome. In the current project, Ben Philpot’s laboratory aims to identify the circuitry and protein pathways underlying seizures in a mouse model of Angelman syndrome, with the goal of identifying disease-modifying targets to treat seizures. The mechanistic insights yielded by these studies may further guide therapeutically oriented investigations of excitatory-inhibitory imbalance across the broader spectrum of ASDs.

A large number of autism risk genes encode proteins that play critical roles in regulating the formation, maturation and function of synaptic connections in the brain, yet the underlying molecular mechanisms of autism are poorly understood. Synaptic connections in the brain consist of the presynaptic axon, the postsynaptic dendrite and the ensheathing astrocytic process. Astrocytes are morphologically complex, non-neuronal cells that play critical roles in synapse assembly, maturation and function.

Animal models play pivotal roles in understanding the relationship between behaviors and underlying brain circuits. One of the key features of autism is a deficit in social communication, including vocal communication. The primary animal models for autism research have been rodents because of the advantage of genetic manipulations. However, rodents lack certain social communication behaviors exhibited by primates, such as eye contact and high-level vocal communication. There is therefore a great need to develop new animal models, preferably nonhuman primate models, for autism research.

Many of the social and cognitive behavioral impairments associated with autism spectrum disorders (ASDs) are likely caused by changes in early brain development that alter the formation of neural circuits, and in particular, the neural circuitry of the cerebral cortex. Because early brain development is completed long before the onset of any identifiable behavioral changes, most studies of the developmental origins of autism have focused on animal models of genetic syndromes or rare single-gene mutations that lead to ASD-like behaviors. It is not clear how these different syndromes may be related to one another, or how these distinct genetic changes can each lead to similar behavioral outcomes.

Chromosomal copy number variations (CNVs) are common genetic abnormalities in autism spectrum disorder (ASD) and have been identified in approximately 10 percent of individuals with ASD. Currently, there is a knowledge gap in the understanding of the molecular and synaptic mechanisms underlying CNV-associated ASD.

Blencowe will identify and characterize small molecules to rescue activity-dependent neuronal microexon splicing, providing a potential therapeutic strategy for autism.

Timothy Roberts and his colleagues at the Children’s Hospital of Philadelphia are studying the responsiveness of neural oscillatory measures to acute administration of STX209 (arbaclofen), a GABAB agonist and a candidate therapeutic for autism spectrum disorder (ASD).

Many children with autism have unusually high numbers of synapses, or connections between neurons, particularly in the cortex, which may result from overgrowth and a disruption of neuronal pruning during childhood. Pruning and reshaping of neurons pares down the number of synapses in the brain while eliminating inappropriate synapses that lead to over-connectivity between brain regions, and possibly inappropriate learning, behavior and seizures. David Sulzer and his colleagues at Columbia University hypothesize that autism-associated mutations in the tuberous sclerosis gene, TSC, can cause over-connectivity when the target of TSC, the mTOR pathway, interferes with normal neuronal pruning.

Opioids have long been implicated in social behaviors. Reducing opioid activity increases affiliative social behaviors and social reward-seeking while lowering stereotypies and self-injurious behaviors. The specific role of opioid blockers in complex social cognition, however, requires more investigation.