Cell-type-specific Synaptic Imbalance and Disrupted Homeostatic Plasticity in Cortical Circuits of ASD-associated Chd8 Haploinsufficient Mice

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2021 Apr 10

PMID 33837267

Citations 17

Authors

Robert A Ellingford

Martyna J Panasiuk

Emilie Rabesahala de Meritens

Raghav Shaunak

Liam Naybour

Lorcan Browne

M Albert Basson

Laura C Andreae

Affiliations

Soon will be listed here.

Abstract

Heterozygous mutation of chromodomain helicase DNA binding protein 8 (CHD8) is strongly associated with autism spectrum disorder (ASD) and results in dysregulated expression of neurodevelopmental and synaptic genes during brain development. To reveal how these changes affect ASD-associated cortical circuits, we studied synaptic transmission in the prefrontal cortex of a haploinsufficient Chd8 mouse model. We report profound alterations to both excitatory and inhibitory synaptic transmission onto deep layer projection neurons, resulting in a reduced excitatory:inhibitory balance, which were found to vary dynamically across neurodevelopment and result from distinct effects of reduced Chd8 expression within individual neuronal subtypes. These changes were associated with disrupted regulation of homeostatic plasticity mechanisms operating via spontaneous neurotransmission. These findings therefore directly implicate CHD8 mutation in the disruption of ASD-relevant circuits in the cortex.

Citing Articles

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Male-Dominant Effects of Chd8 Haploinsufficiency on Synaptic Phenotypes during Development in Mouse Prefrontal Cortex.

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References

Rubenstein J, Merzenich M . Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003; 2(5):255-67. PMC: 6748642. DOI: 10.1034/j.1601-183x.2003.00037.x. View

Nelson S, Valakh V . Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders. Neuron. 2015; 87(4):684-98. PMC: 4567857. DOI: 10.1016/j.neuron.2015.07.033. View

Lee E, Lee J, Kim E . Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders. Biol Psychiatry. 2016; 81(10):838-847. DOI: 10.1016/j.biopsych.2016.05.011. View

De Rubeis S, He X, Goldberg A, Poultney C, Samocha K, Cicek A . Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014; 515(7526):209-15. PMC: 4402723. DOI: 10.1038/nature13772. View

Bourgeron T . From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015; 16(9):551-63. DOI: 10.1038/nrn3992. View

Guang S, Pang N, Deng X, Yang L, He F, Wu L . Synaptopathology Involved in Autism Spectrum Disorder. Front Cell Neurosci. 2019; 12:470. PMC: 6309163. DOI: 10.3389/fncel.2018.00470. View

Jung H, Park H, Choi Y, Kang H, Lee E, Kweon H . Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice. Nat Neurosci. 2018; 21(9):1218-1228. DOI: 10.1038/s41593-018-0208-z. View

Platt R, Zhou Y, Slaymaker I, Shetty A, Weisbach N, Kim J . Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits. Cell Rep. 2017; 19(2):335-350. PMC: 5455342. DOI: 10.1016/j.celrep.2017.03.052. View

Dani V, Nelson S . Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome. J Neurosci. 2009; 29(36):11263-70. PMC: 2765053. DOI: 10.1523/JNEUROSCI.1019-09.2009. View

10.

Dindot S, Antalffy B, Bhattacharjee M, Beaudet A . The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet. 2007; 17(1):111-8. DOI: 10.1093/hmg/ddm288. View

11.

Peixoto R, Wang W, Croney D, Kozorovitskiy Y, Sabatini B . Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-/-) mice. Nat Neurosci. 2016; 19(5):716-724. PMC: 4846490. DOI: 10.1038/nn.4260. View

12.

Silverman J, Oliver C, Karras M, Gastrell P, Crawley J . AMPAKINE enhancement of social interaction in the BTBR mouse model of autism. Neuropharmacology. 2012; 64:268-82. PMC: 3445667. DOI: 10.1016/j.neuropharm.2012.07.013. View

13.

Turrigiano G, Leslie K, Desai N, Rutherford L, Nelson S . Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature. 1998; 391(6670):892-6. DOI: 10.1038/36103. View

14.

Desai N, Rutherford L, Turrigiano G . Plasticity in the intrinsic excitability of cortical pyramidal neurons. Nat Neurosci. 1999; 2(6):515-20. DOI: 10.1038/9165. View

15.

Blackman M, Djukic B, Nelson S, Turrigiano G . A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J Neurosci. 2012; 32(39):13529-36. PMC: 3483036. DOI: 10.1523/JNEUROSCI.3077-12.2012. View

16.

Qiu Z, Sylwestrak E, Lieberman D, Zhang Y, Liu X, Ghosh A . The Rett syndrome protein MeCP2 regulates synaptic scaling. J Neurosci. 2012; 32(3):989-94. PMC: 3711796. DOI: 10.1523/JNEUROSCI.0175-11.2012. View

17.

Zhong X, Li H, Chang Q . MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5. J Neurosci. 2012; 32(37):12841-7. PMC: 3474205. DOI: 10.1523/JNEUROSCI.2784-12.2012. View

18.

Soden M, Chen L . Fragile X protein FMRP is required for homeostatic plasticity and regulation of synaptic strength by retinoic acid. J Neurosci. 2010; 30(50):16910-21. PMC: 3073636. DOI: 10.1523/JNEUROSCI.3660-10.2010. View

19.

Bulow P, Murphy T, Bassell G, Wenner P . Homeostatic Intrinsic Plasticity Is Functionally Altered in Fmr1 KO Cortical Neurons. Cell Rep. 2019; 26(6):1378-1388.e3. PMC: 6443253. DOI: 10.1016/j.celrep.2019.01.035. View

20.

Tatavarty V, Torrado Pacheco A, Groves Kuhnle C, Lin H, Koundinya P, Miska N . Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1. Neuron. 2020; 106(5):769-777.e4. PMC: 7331792. DOI: 10.1016/j.neuron.2020.02.033. View