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Summary of Advances Cover 2016
Summary of Advance
In Autism Spectrum Disorder Research
Question 2: How Can I Understand What Is Happening?

Peripheral mechanosensory neuron dysfunction underlies tactile and behavioral deficits in mouse models of ASDs
Orefice LL, Zimmerman AL, Chirila AM, Sleboda SJ, Head JP, Ginty DD. Cell. 2016 Jul 14;166(2):299-313. [PMID: 27293187]

Unusual or increased sensitivity to touch is a common symptom in individuals with ASD. The experience of touch in early childhood is important for the development of social behaviors and communication, and it is possible that hypersensitivity to touch can contribute to social and communication challenges later in a child’s life.

The brain mechanisms that underlie this increased sensitivity to touch in individuals with ASD are not well understood, but they are thought to have a genetic component. In this study, researchers used several mouse models of ASD to examine genetic contributions to different behaviors and brain functions related to touch.

Mice with mutations in one of four genes that are linked to ASD in humans (Mecp2, Gabrb3, Shank3, and Fmr1) were compared to mice without mutations in those genes. First, the mice were permitted to explore an environment that contained smooth- and rough-textured objects. The control mice preferred to explore different textures, while the mice with ASD-related mutations showed aversion to exploring the differently textured objects. Next, the mice received a light puff of air against the hair on their backs followed by a brief noise to stimulate a startle response (an unconscious response or reflex to a perceived threat). Compared to control mice, mice with ASD-related mutations exhibited an increased startle response, indicating hypersensitivity to touch.

Next, the researchers examined the effect of deleting ASD-linked genes in different types of brain cells. They found that deletion of Mecp2 or Gabrb3 in sensory neurons caused abnormalities in identifying different textures and in touch sensitivity. By recording electrical activity in brain cells that lacked Mecp2 or Gabrb3, the researchers determined that the abnormal touch sensitivity was due to abnormal electrical signals between sensory neurons. Surprisingly, when the researchers restored Mecp2 in just the sensory neurons, the hypersensitivity to touch and aversion to texture was normalized.

Finally, the researchers observed behavioral changes after deleting Mecp2 or Gabrb3. They found that mice lacking either gene displayed anxiety-like behavior, such as an aversion to exploring their environment. The mice also showed impaired social behavior with other mice in a social interaction test. Interestingly, deletion of these genes during developmental stages, but not during adulthood, resulted in increased anxiety and decreased social interactions. Again, restoring expression of Mecp2 normalized the anxiety behaviors and social interactions.

Together, these results indicate that, in mice, the ASD-linked genes Mecp2 and Gabrb3 affect touch sensitivity, and that touch sensitivity may be linked to other ASD traits, such as anxiety and social interaction deficits.

Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism
Parikshak NN, Swarup V, Belgard TG, Irimia M, Ramaswami G, Gandal MJ, Hartl C, Leppa V, Ubieta LT, Huang J, Lowe JK, Blencowe BJ, Horvath S, Geschwind DH. Nature. 2016 Dec 15;540(7633):423-427. [PMID: 27919067]

Research shows that ASD is associated with non-typical genetic patterns (an ASD "genomic signature"), but exactly how genes influence biological and behavioral outcomes in ASD is not well understood. This study aimed to better understand how genetic expression—the instructions that determine an individual’s unique traits and characteristics (also known as a person’s phenotype)—is different in the brains of individuals with ASD. The study further investigated how RNA, which is an important molecule in the transcription and translation of genes, might also regulate genetic expression. Post-mortem studies were performed on 48 individuals with ASD and 49 control group individuals to find patterns of genetic expression specific to ASD.

First, the researchers found significant ASD-related differences in genetic expression in the cortex, the region of the brain important for higher functioning such as language, memory, and learning. In this region, 584 genes had higher expression and 558 genes had lower expression in individuals with ASD as compared to the controls. The degree of difference in genetic expression between individuals with ASD and the control group likely reflects how significantly a particular gene influences phenotype. The genes that had higher expression levels in subjects with ASD were largely present in microglia and astrocytes, which are non-neuronal cells in the central nervous system responsible for regulation and maintenance of neurons. The genes that had lower expression levels in individuals with ASD were largely genes that are specifically expressed in neurons, the brain cells responsible for transmitting and receiving information.

The researchers also determined differences in long noncoding RNAs (lncRNAs), which do not result in expression of a specific protein, but do affect how other genes are expressed. Interestingly, they found differences in 60 lncRNAs in individuals with ASD as compared to the controls. They further found that abnormal regulation of expression and function of lncRNAs is an important component of the ASD genomic signature. Two specific lncRNAs were identified that have decreased expression during development in controls, but increased expression in ASD.

Next, the researchers examined differences in alternative splicing, a regulatory process of gene expression that can result in one gene coding for multiple proteins based on how the RNA sequence is “trimmed.” They found differences in alternative splicing in the cortex of subjects with ASD, which results in the removal of parts of genes that would normally be expressed in neurons.

Additionally, the researchers examined differences in gene expression between the frontal and temporal regions of the cortex. They found 523 genes with differences in expression between the two regions in the control group, but no significant expression differences between regions in the ASD group. This suggests that reduced differences in gene expression across brain regions contribute to the ASD genomic signature.

Together, these data improve our knowledge of the genetic pathways that underlie ASD and indicate that different genetic patterns and pathways may ultimately result in the complex effects of ASD.

Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders
Werling DM, Parikshak NN, Geschwind DH. Nat Commun. 2016 Feb 19;7:10717. [PMID: 26892004]

ASD is more common in males than females, and there are two theories that may provide a biological basis for the difference in prevalence. Given that many genes in the human genome are expressed differentially in males and females, one possibility is that genes associated with ASD (ASD-risk genes) are among the many genes that are differentially expressed based on sex. The other possibility is that the expression of ASD-risk genes is the same between males and females, but that ASD-risk genes interact with sex-specific genes or biological pathways to determine an ASD outcome. In this study, researchers investigated the interaction between ASD-risk genes and sex-specific genes to distinguish between these two possibilities.

First, the researchers analyzed pre-existing data of genomic expression in male and female adult and prenatal brain tissue. They focused specifically on the cerebral cortex, the region of the brain important for complex functions such as learning and language, as this brain region has been shown to have elevated expression levels of ASD-risk genes. Using both adult and prenatal tissue allowed the researchers to identify genes that are differentially expressed based on sex, as well as ASD-risk genes that are typically expressed during development.

When comparing gene expression between male and female adult tissue, the researchers found no known ASD-risk genes that are differentially expressed between males and females. They considered the possibility that a difference may be more evident during development, but when comparing gene expression from prenatal tissue samples, they again saw no difference between males and females. These results suggest that the increased risk of ASD in males is not due to differential expression of known ASD-risk genes between males and females.

Next, the researchers tested the possibility that genes that are abnormally regulated in ASD are differentially expressed in males and females. When comparing gene expression in adult cortex, they found that 67% of genes that are known to have increased expression in ASD are present at higher levels in males than in females. Among these are genes that regulate the function of astrocytes and microglia, which are involved in the development and maintenance of neurons. In contrast, they found that some genes that typically have lower expression in ASD were present at higher levels in females than in males. Among these are genes that are involved in regulation of neural synaptic function. That these genes, which are commonly down-regulated in ASD, are up-regulated in females, suggests that there may be ASD-protective mechanisms in the female genome.

The results from this study support the theory that the difference in prevalence of ASD in males and females is not due to sex-specific differences in ASD-risk genes, but instead due to differences in the way ASD-risk genes interact with sex-specific genes. These differences may ultimately affect the relationships among neurons, astrocytes, and microglia to skew prevalence of ASD towards males.

Question 2

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