The unusually high incidence of cranial and facial anomalies among people with autism may provide insight into the underlying biology of the disorder. Curtis Deutsch of the Eunice Kennedy Shriver Center at the University of Massachusetts Medical School and his colleagues are evaluating these anomalies using new, state-of-the-art imaging technology.
Copy number variants (CNVs) are segments of DNA that vary in copy number between different individuals. CNVs confer significant risk of neuropsychiatric disorders, including autism and schizophrenia. Notably, there appears to be a reciprocal relationship between copy number and brain size for certain genetic loci. For example, deletions of the genomic region 16p11.2 tend to be associated with autism and increased head circumference, whereas duplications of the same segment tend to be associated with schizophrenia and smaller head circumference. The contrasting clinical phenotypes that are associated with reciprocal changes in gene dosage could represent opposite extremes of the same neurodevelopmental process.
The deletion of 27 genes in the 16p11.2 chromosomal region is associated with autism spectrum disorders, intellectual disability and obesity. To study the underlying cellular, molecular and anatomical basis of autism, Ricardo Dolmetsch and his colleagues at Stanford University in California have generated a mouse that lacks the same 27 genes on a corresponding chromosome in the mouse genome. Their goal, in collaboration with Jacqueline Crawley’s lab, is to characterize the neuroanatomical, neurophysiological and behavioral features of these mice.
The etiology of autism is complex and mysterious. Autism has a strong genetic basis but there is remarkable diversity and heterogeneity in genes that are associated with the disorder. Despite this heterogeneity, a convergence of evidence suggests that disruptions in synapse function, neuronal activity and circuit formation are the origin of behaviors associated with autism.
Comprehensive studies of the human genome using high-speed DNA sequencing have identified new genes whose mutations appear to contribute to autism. One class of autism genes consists of regulators of the way that cells, including neurons in the brain, compact their DNA so that it can fit into the nucleus of the cell, while also being available for the selective production of proteins required for brain function. These genes, called chromatin regulators, appear to be among the most frequently mutated genes in individuals with autism. It seems that chromatin regulators control the production of proteins necessary for the development of neural circuits, and perhaps transmission of electrical impulses in the brain.
The activation of extracellular signal-related kinase (ERK), a key enzyme in cellular signaling, may prove to be a useful biomarker in autism, as an aid in early diagnosis, a predictor of treatment response, and perhaps as a predictor of long-term outcomes. ERK is being used as a biomarker in fragile X syndrome because ERK activation is delayed in blood samples of people with the disorder, compared with controls.
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.
Autism arises in early childhood, during a period of intense learning when many of the brain’s connections are modified by experience. Eric Kandel, Yun-Beom Choi and Craig Bailey of Columbia University are using animal models of memory formation to investigate how two autism-associated proteins — neuroligin and neurexin — regulate this process.
The relationship between genetics and autism is not always straightforward, but some autism spectrum disorders are known to be caused by defects in a single gene. These simpler cases give researchers the opportunity to create animal models with the genetic defect and use them to test hypotheses about the mechanisms at work in autism.
Autism arises in early childhood, during a period of intense learning when many of the brain’s connections are modified by experience. Several autism-associated proteins also play important roles in memory formation.