Thomas (TJ) Egeland

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting approximately 1 in 44 children in the US. ASD is characterized by a core triad of sociocommunicative deficits, repetitive behaviors, and restricted interests¹. The disorder is highly heritable with multifactorial genetic, epigenetic, and environmental contributions. Chromodomain-helicase-DNA-binding protein 8 (CHD8) represents the highest frequency high risk ASD gene, with variants accounting for 0.5% of known cases². CHD8 is a chromatin remodeler essential for neurodevelopment. In cells of neural lineage, CHD8 can positively regulate the Wnt / β-catenin signaling pathway^3,4. Here, we examine how Wnt / β-catenin signaling is perturbed in CHD8 variants and how fluoxetine can partially rescue neurogenesis in these variants⁵.

Objectives: In this review, we explored CHD8’s involvement in the Wnt / β-catenin pathway, how variants affect the pathway, and fluoxetine as a potential therapeutic outlet in the context of CHD8 mutations.

Methods: PubMed was searched to identify primary research articles using the keywords “Autism Spectrum Disorder”, “CHD8”, and “Neurodevelopment.” Articles were further refined for relevance. Primary research articles were identified between the years 2017 and 2023. Articles cited before 2017 were utilized to support the conclusions from more recent articles.

Results: CHD8 haploinsufficiency significantly reduces mouse cortical thickness, with the effect persisting into adulthood⁶. CHD8 knockdown was further shown to decrease mean and total dendritic length and cortical dendritic secondary branching⁶. CHD8 haploinsufficiency also impairs social functioning in mice, conferring ASD-like behavioral deficits like increased anxiety-like behaviors (light-dark transition tests) and impaired sociability (social novelty and time tests)⁶. CHD8 acts in concert with the Wnt/β-catenin signaling pathway to promote neuronal development while delaying neuronal specialization. β-catenin has been shown to rescue altered transcription in CHD8 knockdown cortical mouse cells in utero^3,4. Importantly, β-catenin rescued performance across a variety of social tasks in CHD8 knockdown mice, including sociability (as measured by number of entries into a light chamber) and anxiety (as measured by time spent in a chamber with a stranger mouse)^3,4. Fluoxetine treatment has been shown to increase hippocampal neurogenesis, neuronal proliferation, and cortical cell survival, and provide inflammatory protection^7-9. Specifically, L1-INP neuroproginator cells proliferate in cortex following 6 weeks fluoxetine, with proliferation persisting in a dose-dependent manner 8 weeks after dosing is ceased^7,8. Hippocampal cell neurogenesis is partially rescued by the antidepressant fluoxetine, indicating a potential therapeutic avenue in CHD8 deficiency⁵.

Conclusions: Studies have shown that CHD8 is chromatin remodeler essential for neurodevelopment and positively regulates the Wnt / β-catenin signaling pathway. Both hippocampal cell neurogenesis and Wnt / β-catenin signaling are partially rescued in vitro with fluoxetine treatment. Taken together, the axis of CHD8, Wnt / β-catenin signaling, and SSRIs may yield an important therapeutic window in better characterizing both the neurogenic perturbations and genetic basis of ASD.

Works Cited:

1. Guang S, Pang N, Deng X, et al. Synaptopathology Involved in Autism Spectrum Disorder. Front Cell Neurosci. 2018;12:470. doi:10.3389/fncel.2018.00470
2. Dingemans, A.J.M., Truijen, K.M.G., van de Ven, S. et al. The phenotypic spectrum and genotype-phenotype correlations in 106 patients with variants in major autism gene CHD8. Transl Psychiatry 12, 421 (2022). Doi:10.1038/s41398-022-02189-1
3. Nusse R, Clevers H. Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. Jun 01 2017;169(6):985-999. doi:10.1016/j.cell.2017.05.016
4. Durak O, Gao F, Kaeser-Woo YJ, et al. Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. Nat Neurosci. Nov 2016;19(11):1477-1488. doi:10.1038/nn.4400
5. Dong C, Zhao C, Chen X, et al. Conserved and Distinct Functions of the Autism-Related Chromatin Remodeler CHD8 in Embryonic and Adult Forebrain Neurogenesis. J Neurosci. Nov 02 2022;42(44):8373-8392. doi:10.1523/JNEUROSCI.2400-21.2022
6. Xu Q, Liu YY, Wang X, et al. Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons. Mol Autism. 2018;9:65. doi:10.1186/s13229-018-0244-2
7. Yohn CN, Shifman S, Garino A, et al. Fluoxetine effects on behavior and adult hippocampal neurogenesis in female C57BL/6J mice across the estrous cycle. Psychopharmacology (Berl). May 2020;237(5):1281-1290. doi:10.1007/s00213-020-05456-5
8. Ohira K, Takeuchi R, Shoji H, Miyakawa T. Fluoxetine-induced cortical adult neurogenesis. Neuropsychopharmacology. May 2013;38(6):909-20. doi:10.1038/npp.2013.2
9. Sprowles JLN, Hufgard JR, Gutierrez A, et al. Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats. Int J Dev Neurosci. Oct 2017;61:92-111. doi:10.1016/j.ijdevneu.2017.06.004