Nancy Yang

Introduction. Autism spectrum disorders (ASD) include a group of neurodevelopmental disorders characterized by core symptoms of social interaction deficits and restrictive, repetitive patterns of behaviors.² Many ASD risk genes have been identified, and a common ASD-related gene mutation affects the chromodomain helicase DNA-binding protein 8 (CHD8).^1,3,4 CHD8 has many roles, including proper neuronal development and connectivity. Indeed, abnormal neuronal migration, functional connectivity, and myelination have all been identified in ASD study models.^1,2,3,4 Current treatments focus on managing symptoms through behavioral interventions, and no medications directly treat the two core ASD symptoms.^1,2 Oxytocin may prove to be a potential treatment for a subset of ASD patients with known Chd8 mutations.^5,6,7 Methods. Fluorescently labeled cortical neurons of Chd8 heterozygous mutant mice were visualized during pre- and postnatal development.¹ rsfMRI was used to examine connectivity among various brain areas of Chd8 mutant mice, and social interactions were assessed.² DTI analysis of mice having dysfunctional Chd8 in their oligodendrocytes found correlations between functional connectivity and social behaviors.³ Spontaneous excitatory postsynaptic currents (sEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) were also measured via electrophysiology in medium spiny neurons in the nucleus accumbens of Chd8 mutant mice.⁴ Chd8 mutant mice were administered oxytocin intraperitoneally.⁵ In two clinical trials, ASD patients were given intranasal oxytocin.^6,7 Results. Neuronal migration was delayed in the brains of Chd8 mutant mice, although the process eventually caught up.¹ Overconnectivity between the auditory cortex and other cortical areas was seen in Chd8 mutant mice, which may contribute to auditory processing deficits and over-responsivity to sensory stimuli—behaviors seen in ASD.² DTI analysis revealed altered functional connectivity, which was associated with brain structural and behavioral changes.³ Electrophysiology studies showed increased sEPSC and mIPSC frequency and/or amplitude in Chd8 mutant mice, suggesting that local decrease of inhibitory transmission may contribute to enhanced excitatory inputs onto MSNs.⁴ In Chd8 mice, oxytocin restored plasma oxytocin levels and allowed them to overcome anxiety-like behaviors and correct social preferences.⁵ In ASD individuals, there were slight improvements in social functioning, and whole brain analyses revealed reduced amygdala connectivity, particularly to the cortical regions of the “social brain.”^6,7 Conclusions. Oxytocin is a potentially useful therapeutic for a subset of individuals with ASD; however, it remains to be determined whether those most helped by oxytocin have Chd8-related gene mutations. To better guide therapeutic development, future clinical studies should consider mutations in Chd8 as a potential factor in therapeutic response to oxytocin.

1. 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. Published 2018 Dec 19. doi:10.1186/s13229-018-0244-2
2. Suetterlin P, Hurley S, Mohan C, et al. Altered Neocortical Gene Expression, Brain Overgrowth and Functional Over-Connectivity in Chd8 Haploinsufficient Mice. Cereb Cortex. 2018;28(6):2192-2206. doi:10.1093/cercor/bhy058
3. Kawamura A, Abe Y, Seki F, et al. Chd8 mutation in oligodendrocytes alters microstructure and functional connectivity in the mouse brain. Mol Brain. 2020;13(1):160. Published 2020 Nov 23. doi:10.1186/s13041-020-00699-x
4. Platt RJ, Zhou Y, Slaymaker IM, et al. Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits. Cell Rep. 2017;19(2):335-350. doi:10.1016/j.celrep.2017.03.052
5. Cherepanov SM, Gerasimenko M, Yuhi T, et al. Oxytocin ameliorates impaired social behavior in a Chd8 haploinsufficiency mouse model of autism. BMC Neurosci. 2021;22(1):32. Published 2021 May 1. doi:10.1186/s12868-021-00631-6
6. Parker KJ, Oztan O, Libove RA, et al. Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci U S A. 2017;114(30):8119-8124. doi:10.1073/pnas.1705521114
7. Alaerts K, Bernaerts S, Prinsen J, Dillen C, Steyaert J, Wenderoth N. Oxytocin induces long-lasting adaptations within amygdala circuitry in autism: a treatment-mechanism study with randomized placebo-controlled design. 2020;45(7):1141-1149. doi:10.1038/s41386-020-0653-8