Multiple nucleotide variants in the coding sequence of the EFR3A gene are associated with autism, but the protein's function is not well understood. Pietro De Camilli and his colleagues at Yale University have used their expertise in neuronal signaling and cell biology to uncover the role of EFR3A in autism.
Mark Alter and his colleagues at the University of Pennsylvania study the relationship between brain cell maturation and the transcription of genes. Each cell type has its own transcription program, depending on which genes it uses to function. As brain cells mature, they undergo many changes in their cellular transcription programs.
Two central challenges in autism research are defining specific neuronal abnormalities from genetic and environmental contributions and establishing preclinical models with human cells to test potential therapies. Autism is believed to be a disorder of neurodevelopment with a strong genetic liability. A large number of genetic risk loci have been identified by genetic association studies. Various animal models are being developed to explore the function of these genes in regulating neuronal development.
Loss-of-function mutations in the UBE3A gene give rise to Angelman syndrome, a neurodevelopmental disorder characterized by absence of speech, a happy demeanor, cognitive delay, motor deficits and seizures. Chromosomal alterations in 15q11-13, the region that includes UBE3A, have been linked to autism. UBE3A encodes an enzyme that targets a subset of cellular proteins for degradation. Elevated levels of several neuronal proteins have previously been observed in the absence of UBE3A.
Rudolf Jaenisch and his colleagues sought to create a novel platform for studying autism spectrum disorders in human cells. Using cutting-edge gene-editing technology, they introduced mutations into genes that are known to cause disorders on the autism spectrum, such as Rett syndrome and fragile X syndrome. This allowed them, for the first time, to investigate the effects of pathogenic mutations on the morphology, electrophysiology and intracellular signaling of human neurons in culture.
Poor reciprocal social interaction is a devastating behavioral anomaly and a defining feature in people with autism spectrum disorders. Little is known about the cause and mechanisms of social deficits in autism, which hampers the development of effective therapies. Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system. It controls excitatory transmission by binding to a family of receptors, including AMPA receptors. Glutamate signaling defects causing an imbalance in excitatory and inhibitory neuronal circuits are implicated in autism; however, the molecular mechanisms remain unknown. The research teams of Richard Huganir and Tao Wang at Johns Hopkins University in Baltimore propose to study mutations in AMPA-receptor signaling genes that have been found in people with autism and to generate mouse models with these human mutations to investigate mechanisms of social deficits in autism.
Animal models offer opportunities to conduct biological studies in order to identify the mechanisms responsible for autism symptoms. Researchers commonly use the BTBR mouse strain as a model for studying mechanisms that may be responsible for the development of autism, because BTBR mice show many autism-like behaviors.
The genes implicated in autism thus far support the hypothesis that impaired neuronal connectivity may underlie autism pathogenesis. They also suggest that an imbalance between excitatory and inhibitory synapses — the junctions between neurons — during development may play a role in the disorder. Further knowledge of the protein and pathway interactions for the implicated genes is needed for a better understanding of the underlying pathogenic mechanisms of autism.
Individuals with autism have deficits in social and emotional learning. The amygdala, a region of the brain involved in orchestrating emotion and emotional memory, is affected in individuals with autism. The nature of the dysfunction is not well characterized, however. Eric Kandel, Yun-Beom Choi, Craig Bailey and their colleagues at Columbia University Medical Center aim to examine the role of an autism-implicated protein, neurexin, at synapses in the amygdala. They also plan to investigate how neurexin is involved in fear memory, a function that is associated with the amygdala.
Modifications in inhibition mediated by gamma-aminobutyric acid type A receptors (GABAAR) are continually implicated in the etiology of autism. GABAAR receptors mediate both phasic (transient) and tonic inhibition (sustained) forms of chloride-ion-mediated neuronal inhibition. Duplications of and mutations within the receptor’s beta-3 subunit are strongly linked to autism. The functional expression of GABAARs is subject to regulation via phosphorylation of serine residues 408 and 409 within the beta-3 subunit, a covalent modification of protein structure that plays a key role in regulating GABAAR activity.