重视孤独症谱系障碍发生的神经生物学机制

doi:10.11852/zgetbjzz2024-1362

摘要/Abstract

摘要： 孤独症谱系障碍(ASD)是一种常见的儿童神经发育性疾病,其特征为社交沟通障碍和重复刻板行为,全球患病率持续上升。其病因复杂,涉及遗传和环境因素。本文系统总结了关于ASD神经病理机制的研究进展,包括突触功能、神经递质失衡、神经环路异常、神经解剖学变化以及神经炎症等。深入理解ASD的病理机制可为相关临床治疗策略的开发提供科学依据和指导。

关键词: 儿童神经发育, 孤独症谱系障碍, 神经突触, 神经环路

Abstract: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder in children characterized by impairments in social interactions and repetitive, stereotyped behaviors, with a globally increasing incidence rate. Its etiology is complex, involving both genetic and environmental factors. This article systematically summarizes the research progress on the neuropathological mechanisms of ASD, encompassing synaptic function, neurotransmitter imbalance, neural circuit abnormalities, neuroanatomical changes, and neuroinflammation. A deep understanding of the pathological mechanisms of ASD can provide scientific evidence and guidance for the development of related clinical treatment strategies.

Key words: neurodevelopment, autism spectrum disorder, synapse, neural circuit

中图分类号:

R749.94

肖乐, 叶小姗. 重视孤独症谱系障碍发生的神经生物学机制[J]. 中国儿童保健杂志, 2024, 32(12): 1277-1281.

XIAO Le, YE Xiaoshan. Emphasizing the neurobiological mechanisms of autism spectrum disorder[J]. Chinese Journal of Child Health Care, 2024, 32(12): 1277-1281.

参考文献

[1] 美国精神医学学会. 精神障碍诊断与统计手册[M].北京:北京大学出版社: 2015.
[2] Hirota T, King BHJJ. Autism spectrum disorder: A review[J].JAMA,2023, 329(2): 157-168.
[3] Grosvenor LP, Croen LA, Lynch FL, et al. Autism diagnosis among us children and adults, 2011-2022[J]. JAMA,2024, 7(10): e2442218-e.
[4] Zhou H, Xu X, Yan W, et al. Prevalence of autism spectrum disorder in China: A nationwide multi-center population-based study among children aged 6 to 12 years[J].Neurosci Bull, 2020(36): 961-971.
[5] Hansen SN, Schendel DE, Parner ETJJP. Explaining the increase in the prevalence of autism spectrum disorders: The proportion attributable to changes in reporting practices[J].JAMA Pediatr,2015,169(1): 56-62.
[6] Zhuang H, Liang Z, Ma G, et al. Autism spectrum disorder: Pathogenesis, biomarker, and intervention therapy[J]. Med Comm, 2024, 5(3): e497.
[7] Hansen SN, Schendel DE, Francis RW, et al. Recurrence risk of autism in siblings and cousins: A multinational, population-based study[J].J Am Acad Child Adolesc Psychiatry 2019, 58(9): 866-875.
[8] Rosenberg RE, Law JK, Yenokyan G, et al.Characteristics and concordance of autism spectrum disorders among 277 twin pairs[J].Arch Pediatr Adolesc Med,2009, 163(10): 907-914.
[9] Xiong J, Chen S, Pang N, et al. Neurological diseases with autism spectrum disorder: Role of ASD risk genes[J]. Nat Rev Neurosci, 2019(13): 349.
[10] Bourgeron T.From the genetic architecture to synaptic plasticity in autism spectrum disorder[J].Nat Rev Neurosci,2015,16(9): 551-563.
[11] Missler M, Südhof TC. Neurexins:Three genes and 1001 products[J]. Trends Genet, 1998, 14(1): 20-26.
[12] Varghese M, Keshav N, Jacot-Descombes S, et al.Autism spectrum disorder: Neuropathology and animal models[J]. Acta Neuropathol, 2017,134(4): 537-566.
[13] Kasem E, Kurihara T, Tabuchi K.Neurexins and neuropsychiatric disorders[J]. Neurosci Res,2018(127): 53-60.
[14] Dachtler J, Ivorra JL, Rowland TE, et al.Heterozygous deletion of α-neurexin Ⅰ or α-neurexin Ⅱ results in behaviors relevant to autism and schizophrenia[J].Behavioral Neuroscience, 2015, 129(6): 765-776.
[15] Ichtchenko K, Nguyen T, Südhof TC. Structures, alternative splicing, and neurexin binding of multiple neuroligins[J]. J Biol Chem, 1996, 271(5): 2676-2682.
[16] Hörnberg H, Pérez-Garci E, Schreiner D, et al. Rescue of oxytocin response and social behaviour in a mouse model of autism[J]. Nature, 2020, 584(7820): 252-256.
[17] Uchigashima M, Cheung A, Futai K. Neuroligin-3: A circuit-specific synapse organizer that shapes normal function and autism spectrum disorder-associated dysfunction[J]. Front Mol Neurosci, 2021, 14: 749164.
[18] Tu JC, Xiao B, Naisbitt S, et al. Coupling of mGluR/Homer and PSD-95 complexes by the shank family of postsynaptic density proteins[J]. Neuron, 1999, 23(3): 583-592.
[19] Orefice LL, Mosko JR, Morency DT, et al.Targeting peripheral somatosensory neurons to improve tactile-related phenotypes in ASD models [J]. Cell, 2019, 178(4): 867-886.e24.
[20] De La Torre-Ubieta L, Won H, Stein JL, et al. Advancing the understanding of autism disease mechanisms through genetics[J]. Nat Med, 2016, 22(4): 345-361.
[21] Bagni C, Zukin RS. A synaptic perspective of fragile X syndrome and autism spectrum disorders[J]. Neuron, 2019, 101(6): 1070-1088.
[22] Bourgeron T. A synaptic trek to autism[J]. Curr Opin Neurobiol, 2009, 19(2): 231-234.
[23] Yeung KS, Tso WWY, Ip JJK, et al.Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism[J].Mol Autism, 2017(8): 66.
[24] Zhang J, Zhang JX, Zhang QL.PI3K/AKT/mTOR-mediated autophagy in the development of autism spectrum disorder[J]. Brain Res Bull, 2016(125): 152-158.
[25] Neves-Pereira M, Müller B, Massie D, et al. Deregulation of EIF4E: A novel mechanism for autism[J]. J Med Genet, 2009, 46(11): 759-765.
[26] Astorkia M, Liu Y, Pedrosa EM, et al. Molecular and network disruptions in neurodevelopment uncovered by single cell transcriptomics analysis of CHD8 heterozygous cerebral organoids[J]. Heliyon, 2024, 10(14): e34862.
[27] Paulsen B, Velasco S, Kedaigle AJ, et al. Autism genes converge on asynchronous development of shared neuron classes[J]. Nature, 2022, 602(7896): 268-273.
[28] Lord C, Brugha TS, Charman T, et al. Autism spectrum disorder[J]. Nat Rev Dis Primers, 2020, 6(1): 5.
[29] Ye X, Zhou Q, Ren P, et al. The synaptic and circuit functions of vitamin d in neurodevelopment disorders[J]. Neuropsychiatr Dis Treat, 2023(19): 1515-1530.
[30] Nelson SB, Valakh V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders[J]. Neuron, 2015, 87(4): 684-698.
[31] Zhang L, Huang CC, Dai Y, et al. Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios[J].Transl Psychiatry, 2020, 10(1): 9.
[32] Yang JQ, Yang CH, Yin BQ. Combined the GABA-A and GABA-B receptor agonists attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism[J]. Behav Brain Res,2021(403): 113094.
[33] Cox A, Kohls G, Naples AJ, et al. Diminished social reward anticipation in the broad autism phenotype as revealed by event-related brain potentials[J]. Soc Cogn Affect Neurosci, 2015, 10(10): 1357-1364.
[34] Bartolotti J, Sweeney JA, Mosconi MW. Functional brain abnormalities associated with comorbid anxiety in autism spectrum disorder[J]. Dev Psychopathol, 2020, 32(4): 1273-1286.
[35] Folkes OM, Báldi R, Kondev V, et al. An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability[J].J Clin Invest,2020, 130(4): 1728-1742.
[36] Krüttner S, Falasconi A, Valbuena S, et al. Absence of familiarity triggers hallmarks of autism in mouse model through aberrant tail-of-striatum and prelimbic cortex signaling[J].Neuron, 2022, 110(9): 1468-1482.e5.
[37] Hazlett HC, Gu H, Munsell BC, et al. Early brain development in infants at high risk for autism spectrum disorder [J]. Nature, 2017, 542(7641): 348-351.
[38] Sacco R, Gabriele S, Persico AM. Head circumference and brain size in autism spectrum disorder: A systematic review and meta-analysis[J].Psychiatry Res, 2015, 234(2): 239-251.
[39] Schumann CM, Bloss CS, Barnes CC, et al. Longitudinal magnetic resonance imaging study of cortical development through early childhood in autism[J].J Neurosci, 2010, 30(12): 4419-4427.
[40] Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism[J]. JAMA, 2003, 290(3): 337-344.
[41] Hutsler JJ, Zhang H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders [J]. Brain Res, 2010(1309): 83-94.
[42] Prem S, Millonig JH, Dicicco-Bloom E. Dysregulation of neurite outgrowth and cell migration in autism and other neurodevelopmental disorders[J].Adv Neurobiol, 2020(25): 109-153.
[43] Soiza-Reilly M, Commons KG. Unraveling the architecture of the dorsal raphe synaptic neuropil using high-resolution neuroanatomy[J]. Front Neural Circuits, 2014(8): 105.
[44] Sun F, Chen Y, Gao Q, et al. Abnormal gray matter structure in children and adolescents with high-functioning autism spectrum disorder[J].Psychiatry Res Neuroimaging, 2022(327): 111564.
[45] Fuster JM. The prefrontal cortex--an update: Time is of the essence[J]. Neuron, 2001,30(2): 319-333.
[46] Gu X, Hof PR, Friston KJ, et al. Anterior insular cortex and emotional awareness[J]. J Comp Neurol, 2013, 521(15): 3371-388.
[47] Hazlett HC, Poe MD, Gerig G, et al. Early brain overgrowth in autism associated with an increase in cortical surface area before age 2 years[J]. Arch Gen Psychiatry, 2011, 68(5): 467-476.
[48] Halliday AR, Vucic SN, Georges B, et al. Heterogeneity and convergence across seven neuroimaging modalities: A review of the autism spectrum disorder literature[J]. Frontiers Psychiatry, 2024(15): 1474003.
[49] Yang C, Wang XK, Ma SZ, et al. Abnormal functional connectivity of the reward network is associated with social communication impairments in autism spectrum disorder: A large-scale multi-site resting-state fMRI study[J]. J Affect Disord, 2024(347): 608-618.
[50] Eilam-Stock T, Xu P, Cao M, et al. Abnormal autonomic and associated brain activities during rest in autism spectrum disorder[J]. Brain, 2014, 137(Pt1): 153-171.
[51] Fan J, Bernardi S, Van Dam NT, et al. Functional deficits of the attentional networks in autism[J]. Brain Behav, 2012, 2(5): 647-660.
[52] He C, Chen Y, Jian T, et al. Dynamic functional connectivity analysis reveals decreased variability of the default-mode network in developing autistic brain[J]. Autism Res, 2018, 11(11): 1479-1493.
[53] Frye RE, Cakir J, Rose S, et al. Mitochondria may mediate prenatal environmental influences in autism spectrum disorder[J]. J Pers Med, 2021, 11(3) :218.
[54] Walter C, Marada A, Suhm T, et al. Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery[J]. Nat Commun,2021,12(1): 4284.
[55] Lamanna J, Meldolesi J. Autism spectrum disorder: Brain areas involved, neurobiological mechanisms, diagnoses and therapies[J].Int J Mol Sci,2024,25(4):2423.
[56] Henze K, Martin W. Evolutionary biology: Essence of mitochondria[J]. Nature, 2003, 426(6963): 127-128.
[57] Gyllenhammer LE, Rasmussen JM, Bertele N, et al. Maternal inflammation during pregnancy and offspring brain development: The role of mitochondria[J]. Biol Psychiatry Cogn Neurosci Neuroimaging, 2022, 7(5): 498-509.
[58] Allen M, Huang BS, Notaras MJ, et al. Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca(2+) signaling[J]. Molecular Psychiatry, 2022, 27(5): 2470-2484.
[59] Xiong Y, Chen J, Li Y. Microglia and astrocytes underlie neuroinflammation and synaptic susceptibility in autism spectrum disorder[J]. Frontiers in Neuroscience, 2023(17): 1125428.
[60] Kern JK, Geier DA, Sykes LK, et al. Relevance of neuroinflammation and encephalitis in autism[J].Front Cell Neurosci, 2015(9): 519.
[61] Umpierre AD, Wu LJ. How microglia sense and regulate neuronal activity[J]. Glia, 2021, 69(7): 1637-1653.
[62] Sarn N, Thacker S, Lee H, et al. Germline nuclear-predominant PTEN murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity[J].Mol Autism, 2021, 12(1): 41.
[63] Smith SE, Li J, Garbett K, et al. Maternal immune activation alters fetal brain development through interleukin-6[J].J Neurosci, 2007, 27(40): 10695-10702.
[64] Rangel-Gomez M, Alberini CM, Deneen B, et al. Neuron-Glial interactions: Implications for plasticity, behavior, and cognition[J].J Neurosci, 2024, 44(40):e1231242024.
[65] Broek JA, Guest PC, Rahmoune H, et al. Proteomic analysis of post mortem brain tissue from autism patients: Evidence for opposite changes in prefrontal cortex and cerebellum in synaptic connectivity-related proteins[J].Mol Autism,2014(5):41.
[66] Edmonson C, Ziats MN, Rennert OM. Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum[J].Mol Autism,2014,5(1): 3.
[67] Barón-Mendoza I, García O, Calvo-Ochoa E, et al. Alterations in neuronal cytoskeletal and astrocytic proteins content in the brain of the autistic-like mouse strain C58/J[J]. Neuroscience letters, 2018(682): 32-38.
[68] Bronzuoli MR, Facchinetti R, Ingrassia D, et al. Neuroglia in the autistic brain: Evidence from a preclinical model[J]. Mol Autism,2018(9): 66.
[69] Wang Q, Kong Y, Wu DY, et al.Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors inmice[J].Nat Commun,2021,12(1): 3321.