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Eukaryon

CHD8 Mutants: Balancing Behavior with Unbalanced Genes

Sarah Applebey
Lake Forest College
Lake Forest, Illinois 60045

Decreased CHD8 protein creates an autistic phenotype in humans, but researchers have not fully evaluated the behavioral effects of CHD8 reduction or determined brain regions that mediate these behaviors. Platt et al. (2017) demonstrate a role for the nucleus accumbens in CHD8 mutant mice.

Most organisms actively evade falling, but the mutant mice created in Feng Zhang’s lab are particularly skilled at learning to balance on a rotating cylinder. This is one of the many autistic behaviors assessed in Platt et al. (2017), who characterized a new mouse model of autism1. In humans, ASD is characterized by repetitive and restrictive behaviors, as well as verbal and nonverbal social impairment2. However, as autism lies on a spectrum, the severity of these symptoms varies across individuals and a diverse collection of genes mediates these symptoms. Despite these challenges, clinical subtypes have been identified and related to specific genetic mutations. Platt et al. model a particular subtype identified in human patients, in which, in addition to the typical ASD symptoms, patients have large heads, gastrointestinal problems, and intellectual disability3.

This subtype is caused by one mistake in a genetic recipe that directs the production of a protein termed CHD8. Typically each organism has two copies of the recipe, both used continuously to each contribute to a cumulative amount of protein. When one copy is deleted, less protein is produced. The protein CHD8 is a chromatin remodeler, acting as a director and informing cooks to stop following some recipes or start following others. When there is less CHD8, certain products are made unnecessarily, while other proteins never reach the metaphorical dinner table4. This is certainly problematic because CHD8 is expressed during development and regulates ASD-risk genes5. During typical development, many of these developmental genes direct brain expansion, influencing the number and type of neural cells (neurons), telling neurons where they should reside in the brain, and directing what neurons to communicate with. However, when there is less CHD8, such as in a research-generated mouse model, brain volume, particularly in cerebral cortex, hippocampus, and amygdala, is increased5.

Although previous papers demonstrated CHD8 regulated ASD-risk genes during development, prior to the beginning of the authors experiments, the recipe for CHD8 had not been manipulated in a mouse model. However, other authors beat them to the punch and published papers characterizing behaviors of CHD8 mutant mice, who lacked one functioning CHD8 recipe. These mutants were more anxious and displayed social impairment6, but not all behavioral characteristics of ASD had been assessed, and the specific brain regions controlling these aberrant behaviors had never before been assessed.

When Platt et al., (2017) designed CHD8 mutations missing one recipe for CHD8, they predicted CHD8 mutations would cause ASD-like behaviors and disrupt the production of certain genes. Like the children studied in Bernier et al. (2014), the mice also had larger head sizes and brain volumes (Figure 1A). Authors then quantified what protein production was disrupted compared to siblings without the mutation. Although CHD8 mutant mice had differential protein production in some regions of the brain, overall, the neurons had all received the correct instruction regarding where to reside, what type of neuron to be, and what regions of the brain to interact with. Enticed by the set of dysregulated proteins found in a region called the nucleus accumbens, a brain region linked to conditioned reward-seeking, researchers further explored neuronal activity in that region.

 To determine if this protein dysregulation affected communication between cells, authors listened to messages sent to medium spiny neurons (MSNs) in the nucleus accumbens. As shown in Figure 1B, these neurons were named after their unique shape. By recording these signals, authors noticed that messages telling MSNs to “go” were louder in mutant mice than messages sent in typical mice. Further eavesdropping revealed that quieting signals were decreased, contributing to the louder “go” messages sent onto MSNs.

The research team also evaluated behavioral effects of CHD8 deletion using various tests to assess characteristics of ASD, like sociability and repetitive behaviors. For instance, when given the opportunity to meet a novel mouse, most typical mice will sniff the new animal, but CHD8 mutants preferred to ignore this mouse, indicative of social impairment. As anxiety also sometimes accompanies ASD8, Platt et al., also tested mice for anxiety-like behaviors. When placed in a wide, open box, mutant mice hid near walls of the box rather than following the example of usual mice, who scrambled to explore the area. In addition, when researcher measured grooming as an assessment of the repetitive behavior seen in the ASD patients, the mutant mice did not display this trait. Together, these tests show CHD8 mutant mice were more anxious and less sociable but did not have difficulty learning and recalling negative experiences or engage in repetitive behaviors (Figure 1C).

Platt et al. (2017) also used an unusual behavioral test to examine acquired motor learning. Adult mice were placed on a horizontal cylinder, rotating just high enough above the cage floor, that mice would balance to avoid falling off. Across several days of practice, mutant mice improved more rapidly than control mice, balancing on the cylinder for longer and longer periods. The mutant mice had an enhanced ability to learn motor skills. To find the region of the brain controlling this behavior, the researchers selectively deleted a copy of CHD8 in the nucleus accumbens of normal adult mice. When these mutant mice were placed on the cylinder, they too learned to balance much more quickly compared to the typical adult mouse. Yet, mutant mice with nucleus accumbens-specific CHD8 reduction were not anxious or socially impaired. These novel finding showed that nucleus accumbens determined motor learning, even during adulthood, but did not regulate anxiety or impaired sociability seen in mutant mice.

Although CHD8 production peaks during the early stages of brain development, manipulating levels of CHD8 protein in the nucleus accumbens of adult rats did affect motor learning8. The authors do not evaluate the effects of reduced CHD8 expression during development, so one can only conclude the adult nucleus accumbens is responsible for acquired motor learning. However, it is plausible that this mutation is also responsible for behaviors that are more malleable during development, but not during adulthood, such as anxiety and social impairment. For instance, the nucleus accumbens mediates social reward9, and CHD8 mutations may impair sociability when the deletion occurs during development, but not when it takes place during adulthood. To confirm this, Platt et al. (2017) should have also selectively deleted CHD8 in the nucleus accumbens during development to determine what behaviors were affected. Additionally, one cannot yet state the increased spontaneous activity of MSNs in the nucleus accumbens directly affects the increased acquired motor learning. To further assess this, Platt et al. (2017) should have also recorded MSN’s in the nucleus accumbens of the mice who experienced decreased CHD8 levels only during adulthood.

Nevertheless, this study opens the door for other researchers to evaluate which regions of the brain control aberrant ASD-like behaviors in CHD8 mutant mice. While within the nucleus accumbens CHD8 mutations caused an increase in spontaneous firing of medium spiny neurons and was the source of acquired motor learning, the causes of other behavioral deficits have yet to be explored. Additionally, for the first time Platt et al. (2017) evaluated the effects of CHD8 mutation on neural activity and demonstrated that the nucleus accumbens plays a role in CHD8-mediated ASD-like behavior.

I began writing the News & Views article 1.5 weeks prior to the due date, as it would help my understanding of the capsule presentation. First, I wrote the middle of the paper to make sure I had an understanding of the material and would be able to decide how to link the background to the content of the paper. I briefly went to walk-in hours at the writing center, because I had trouble combining an exciting introduction sentence, making sure I cited the paper discussed first, but then connecting this to a broad background. I also enjoyed writing the discussion paragraphs and being able to critique the paper. However, it was jarring to have to reduce such a complicated paper to more simple language; after initially writing the paper using scientific language, I returned to simplify the wording and add metaphors.

 

References

Platt, R. J., Zhou, Y., Slaymaker, I. M., Shetty, A. S., Weisbach, N. R., Kim, J. A., … & Crabtree, G. R. (2017). Chd8 mutation leads to autistic-like behaviors and impaired striatal circuits. Cell Reports, 19, 335-350. doi: 10.1016/j.celrep.2017.03.052

Shattuck, P. T., Seltzer, M. M., Greenberg, J. S., Orsmond, G. I., Bolt, D., Kring, S., … & Lord, C. (2007). Change in autism symptoms and maladaptive behaviors in adolescents and adults with an autism spectrum disorder. Journal of autism and developmental disorders, 37(9), 1735-1747. doi:10.1007/s10803-013-1913-9

Bernier, R., Golzio, C., Xiong, B., Stessman, H. A., Coe, B. P., Penn, O., … & Schuurs-Hoeijmakers, J. H. (2014). Disruptive CHD8 mutations define a subtype of autism early in development. Cell, 158, 263-276. doi: 10.1016/j.cell.2014.06.017

Kunkel, G. R., Tracy, J. A., Jalufka, F. L., & Lekven, A. C. (2018). CHD8short, a naturally-occurring truncated form of a chromatin remodeler lacking the helicase domain, is a potent transcriptional coregulator. Gene, 641, 303-309.

Cotney, J., Muhle, R. A., Sanders, S. J., Liu, L., Willsey, A. J., Niu, W., … & Reilly, S. K. (2015). The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nature Communications, 6, 6404. doi:

Katayama, Y., Nishiyama, M., Shoji, H., Ohkawa, Y., Kawamura, A., Sato, T., … & Nakayama, K. I. (2016). CHD8 haploinsufficiency results in autistic-like phenotypes in mice. Nature, 537(7622), 675. doi: 10.1038/nature19357

White, S. W., Oswald, D., Ollendick, T., & Scahill, L. (2009). Anxiety in children and adolescents with autism spectrum disorders. Clinical Psychology Review, 29, 216-229.

Gompers, A. L., Su-Feher, L., Ellegood, J., Copping, N. A., Riyadh, M. A., Stradleigh, T. W., … & Zdilar, I. (2017). Germline Chd8 haploinsufficiency alters brain development in mouse. Nature Neuroscience, 20, 1062.

Dölen, G., Darvishzadeh, A., Huang, K. W., & Malenka, R. C. (2013). Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature, 501, 179. doi: 10.1038/nature12518

 

Figures

Applebey Fig 1Figure 1. Compared to typical siblings (top), mutant mice with one functioning CHD8 gene (bottom) display dysfunctional behavior and neural communication. (A) CHD8 mutant mice have enlarged heads. (B) Recording from mediums spiny neurons within the nucleus accumbens demonstrate CHD8 mutant mice have an increase in spontaneous activity due to a reduction in inhibitory signals. (C) As evaluated by a choice test between novel or familiar mice, exploration activity in an open box, and balancing on a rotating cylinder, CHD8 mutant mice display social impairment, anxiety, and increased acquired motor learning, respectively.

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