Role of Glia Cells in Autism Spectrum Disorders

Year 2023, Volume: 15 Issue: 4, 577 - 588, 25.12.2023

Melis Elif Elçi Miraç Barış Usta Koray Karabekiroğlu

https://doi.org/10.18863/pgy.1189139

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an increasing frequency, manifested by functional disorders in social communication and social interaction, limited interests, and repetitive behaviors. The etiology of autism spectrum disorder has not yet been fully elucidated and there are many areas that need further study. Increasing studies have shown that disruptions in synaptic functions are critical in the onset of ASD. Glial cells have a role in the regulation of synaptic functions. In ASD, changes are seen in the number of neurons and glia cells in the affected cerebral cortex, and these changes cause dysregulation in synaptic functions and affect behaviors. Studies provide information about the role of glia cells in the pathophysiology of ASD, but more data is needed on the relationship between ASD and glia cells. In this review, the importance of glial cells in the etiopathogenesis of ASD and studies will be discussed.

Keywords

Glia cells, astroglia, neurons, autism spectrum disorder

Otizm Spektrum Bozukluklarında Glia Hücrelerinin Rolü

Abstract

Otizm spektrum bozukluğu (OSB), sıklığı giderek artmakta olan, sosyal iletişim ve sosyal etkileşimde işlevsel bozukluklar, sınırlı ilgi alanları, tekrarlayan davranışlar ile kendini gösteren nörogelişimsel bir bozukluktur. Otizm spektrum bozukluğu etiyolojisi henüz tam olarak aydınlatılamamıştır ve daha fazla çalışmaya ihtiyaç olan birçok alan vardır. Artan çalışmalar sinaptik fonksiyonlardaki bozulmaların OSB başlangıcında kritik öneme sahip olduğunu göstermiştir. Sinaptik fonksiyonların düzenlenmesinde glial hücrelerin rolü bulunmaktadır. OSB’ de etkilenen serebral kortekste nöron ve glia hücre sayılarında değişiklikler görülmekte, bu değişiklikler sinaptik fonksiyonlarda düzensizliğe yol açmakta ve davranışları etkilemektedir. Yapılan çalışmalar glia hücrelerinin OSB patofizyolojisinde ki rolü ile ilgili bilgiler sunmakta ancak OSB ile glia hücreleri arasında ki ilişki ile ilgili daha çok veriye ihtiyaç duyulmaktadır. Bu derlemede glial hücrelerin OSB etiyopatogenezindeki önemine ve yapılan çalışmalara değinilecektir.

Keywords

Glia hücreleri, astrogilia, nöron, otizm spektrum bozukluğu

References

• Aabed K, Bhat RS, Al-Dbass A, Moubayed N, Algahtani N, Merghani NM et al. (2019) Bee pollen and propolis improve neuroinflammation and dysbiosis induced by propionic acid, a short chain fatty acid in a rodent model of autism. Lipids Health Dis, 18:200.
• Adamsky A, Kol A, Kreisel T, Doron A, Ozeri-Engelhard N, Melcer T et al. (2018) Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell, 174:59-71.
• Aida T, Yoshida J, Nomura M, Tanimura A, Iino Y, Soma M et al. (2015) Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice. Neuropsychopharmacology, 40:1569-1579.
• Amaral DG, Schumann CM, Nordahl CW (2008) Neuroanatomy of autism. Trends Neurosci, 31:137-145.
• Ameis SH, Lerch JP, Taylor MJ, Lee W, Viviano JD, Pipitone J et al. (2016) A diffusion tensor imaging study in children with ADHD, autism spectrum disorder, OCD and matched controls distinct and non-distinct white matter disruption and dimensional brain-behavior relationships. Am J Psychiatry, 173: 1213-1222.
• Amina S, Falcone C, Hong T, Wolf-Ochoa MW, Vakilzadeh G, Allen E et al. (2021) Chandelier cartridge density is reduced in the prefrontal cortex in autism. Cereb Cortex, 31:2944-2951.
• APA (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Washington DC, American Psychiatric Association.
• Aronson M, Hagberg B, Gillberg C (1997) Attention deficits and autistic spectrum problems in children exposed to alcohol during gestation, a follow‐up study. Dev Med Child Neurol Suppl, 39:583-587.
• Bedford SA, Park MTM, Devenyi GA, Tullo S, Germann J, Patel R et al. (2020) Large-scale analyses of the relationship between sex, age and intelligence quotient heterogeneity and cortical morphometry in autism spectrum disorder. Mol Psychiatry, 25:614-628.
• Bergles DE, Roberts JDB, Somogyi P, Jahr CE (2000) Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature, 405:187-191.
• Block CL, Eroglu O, Mague SD, Smith CJ, Ceasrine AM, Sriworarat C et al. (2022) Prenatal environmental stressors impair postnatal microglia function and adult behavior in males. Cell Rep, 40:111161.
• Block ML, Calderón-Garcidueñas L (2009) Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci, 32:506-516.
• Bolton JL, Marinero S, Hassanzadeh T, Natesan D, Le D, Belliveau C et al. (2017) Gestational exposure to air pollution alters cortical volume, microglial morphology, and microglia-neuron interactions in a sex-specific manner. Front Synaptic Neurosci, 9:10.
• Bolton P, Macdonald H, Pickles A, Rios PA, Goode S, Crowson M et al. (1994) A case‐control family history study of autism. J Child Psychol Psychiatry , 35:877-900.
• Bougeard C, Picarel-Blanchot F, Schmid R, Campbell R, Buitelaar J (2021) Prevalence of autism spectrum disorder and co-morbidities in children and adolescents: A systematic literature review. Front Psychiatry , 12:744709.
• Bradl M, Lassmann H (2010)Oligodendrocytes: biology and pathology. Acta Neuropathol, 119:37-53.
• Carniglia L, Ramírez D, Durand D, Saba J, Turati J, Caruso C et al. (2017) Neuropeptides and microglial activation in inflammation, pain, and neurodegenerative diseases. Mediators Inflamm, 2017:5048616.
• Carper RA, Moses P, Tigue ZD, Courchesne E (2002) Cerebral lobes in autism: early hyperplasia and abnormal age effects. Neuroimage , 16:1038-1051.
• Chantler J, Smyrnis L, Tai G (1995) Selective infection of astrocytes in human glial cell cultures by rubella virus. Lab Invest, 72:334-340.
• Choudhury PR, Lahiri S, Rajamma U (2012) Glutamate mediated signaling in the pathophysiology of autism spectrum disorders. Pharmacol Biochem Behav, 100:841-849.
• Christianson AL, Chester N, Kromberg JG (1994) Fetal valproate syndrome: clinical and neuro‐developmental features in two sibling pairs. Dev Med Child Neurol, 36:361-369.
• Chrobak AA, Soltys Z (2017) Bergmann glia, long-term depression, and autism spectrum disorder. Mol Neurobiol, 54:1156-1166.
• Codagnone MG, Podestá MF, Uccelli NA, Reinés A (2015) Differential local connectivity and neuroinflammation profiles in the medial prefrontal cortex and hippocampus in the valproic acid rat model of autism. Dev Neurosci, 37:215-231.
• Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ et al. (2011) Neuron number and size in prefrontal cortex of children with autism. JAMA, 306:2001-2010.
• Cregg JM, DePaul MA, Filous AR, Lang BT, Tran A, Silver J (2014) Functional regeneration beyond the glial scar. Exp Neurol, 253:197-207.
• Cryan JF, O'Riordan KJ, Cowan CS, Sandhu KV, Bastiaanssen TF, Boehme M et al. (2019) The microbiota-gut-brain axis. Physiol Rev, 99:1877-2013.
• De Punder K, Pruimboom L (2015) Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability. Front Immunol, 6:223.
• Depino AM (2013) Peripheral and central inflammation in autism spectrum disorders. Mol Cell Neurosci, 53:69-76.
• Derecki NC, Cronk JC, Kipnis J (2013) The role of microglia in brain maintenance: implications for Rett syndrome. Trends Immunol , 34:144-150.
• DiCarlo GE, Aguilar JI, Matthies HJ, Harrison FE, Bundschuh KE, West A et al. (2020) Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors. J Clin Investig, 129:3407-3419.
• Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD (2007) Conditional knock-out of Kir4. 1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation, J Neurosci, 27:11354-11365.
• Edmonson C, Ziats MN, Rennert OM (2014) Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Mol Autism , 5:3.
• Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E et al. (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci, 18:965-977.
• Escartin C, Rouach N (2013) Astroglial networking contributes to neurometabolic coupling. Front Neuroenergetics, 5:4.
• Eshraghi RS, Davies C, Iyengar R, Perez L, Mittal R, Eshraghi AA (2020) Gut-induced inflammation during development may compromise the blood-brain barrier and predispose to autism spectrum disorder. J Clin Med, 10:27.
• Falcone C, Mevises NY, Hong T, Dufour B, Chen X, Noctor SC et al. (2021) Neuronal and glial cell number is altered in a cortical layer-specific manner in autism. Autism 25:2238-2253.
• Fatemi SH, Folsom TD, Reutiman TJ, Lee S (2008) Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism. Synapse, 62:501-507.
• Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry, 52:805-810.
• Fatemi SH, Folsom TD, Reutiman TJ, Sidwell RW (2008) Viral regulation of aquaporin 4, connexin 43, microcephalin and nucleolin. Schizophr Res , 98:163-177.
• Franco R , Fernandez-Suarez D (2015) Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol, 131:65-86.
• Franklin RJ, Goldman SA (2015) Glia disease and repair—remyelination. Cold Spring Harb Perspect Biol, 7:a020594.
• Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S et al. (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 330:841-845.
• Graciarena M, Seiffe A, Nait-Oumesmar B, Depino AM (2019) Hypomyelination and oligodendroglial alterations in a mouse model of autism spectrum disorder. Front Cell Neurosci, 12:517.
• Guizzetti M, Moore NH, Giordano G, VanDeMark KL, Costa LG (2010) Ethanol inhibits neuritogenesis induced by astrocyte muscarinic receptors. Glia, 58:1395-1406.
• Gzielo K , Nikiforuk A (2021) Astroglia in autism spectrum disorder. Int J Mol Sci 22:11544.
• Gzielo K, Soltys Z, Rajfur Z, Setkowicz Z (2019) The impact of the ketogenic diet on glial cells morphology. A quantitative morphological analysis. Neuroscience, 413:239-251.
• Haida O, Al Sagheer T, Balbous A, Francheteau M, Matas E, Soria F et al. (2019) Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism. Transl Psychiatry, 9:1-12.
• Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci, 10:1387-1394.
• Hansel C (2019)Deregulation of synaptic plasticity in autism. Neurosci Lett, 688:58-61.
• Harry GJ, Kraft AD (2012) Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology, 33:191-206.
• Hartline D, Colman D (2007) Rapid conduction and the evolution of giant axons and myelinated fibers. Curr Biol, 17:R29-R35.
• Horder J, Petrinovic MM, Mendez MA, Bruns A, Takumi T, Spooren W et al. (2018) Glutamate and GABA in autism spectrum disorder—a translational magnetic resonance spectroscopy study in man and rodent models. Transl Psychiatry, 8:106.
• Hughes JR (2007) Autism: the first firm finding= underconnectivity? Epilepsy Behav, 11:20-24.
• Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al. (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med , 4:147ra111.
• Innis SM, Dyer RA (2002) Brain astrocyte synthesis of docosahexaenoic acid from n-3 fatty acids is limited at the elongation of docosapentaenoic acid. J Lipid Res, 43:1529-1536.
• Jeste SS, Geschwind DH (2014) Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nat Rev Neurol, 10:74-81.
• Jia YF, Wininger K, Ho AMC, Peyton L, Baker M, Choi DS (2020) Astrocytic glutamate transporter 1 (GLT1) deficiency reduces anxiety-and depression-like behaviors in mice. Front Behav Neurosci, 14:57.
• Jia YF, Wininger K, Peyton L, Ho AMC, Choi DS (2021) Astrocytic glutamate transporter 1 (GLT1) deficient mice exhibit repetitive behaviors. Behav Brain Res, 396:112906.
• Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O et al. (2017) Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry, 22:273-279.
• Kettenmann H, Verkhratsky A (2011) Neuroglia--living nerve glue. Fortschr Neurol Psychiatr , 79:588-597.
• Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron, 77:10-18.
• Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT (2018) Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement Transl Res Clin Interv, 4:575-590.
• Laurence J Fatemi S (2005) Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum, 4:206-210.
• Li K, Li J, Zheng J, Qin S (2019) Reactive astrocytes in neurodegenerative diseases. Aging Dis, 10:664.
• Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM et al. (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol, 207:111-116.
• Mahmoud S, Gharagozloo M, Simard C, Gris D (2019) Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cell J, 8:184.
• Malkova NV, Collin ZY, Hsiao EY, Moore MJ, Patterson PH (2012) Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun , 26:607-616.
• Marotta R, Risoleo MC, Messina G, Parisi L, Carotenuto M, Vetri L et al. (2020) The neurochemistry of autism. Brain Sci, 10:163.
• Matta SM, Hill-Yardin EL, Crack PJ (2019) The influence of neuroinflammation in Autism Spectrum Disorder. Brain Behav Immun, 79:75-90.
• Matta SM, Moore Z, Walker FR, Hill-Yardin EL, Crack PJ (2020) An altered glial phenotype in the NL3R451C mouse model of autism. Sci Rep, 10:1-13.
• Mefford HC, Batshaw ML, Hoffman EP (2012) Genomics, intellectual disability, and autism. N Engl J Med, 366:733-743.
• Meyer U (2014) Prenatal poly (i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry, 75:307-315.
• Mony TJ, Lee JW, Dreyfus C, DiCicco-Bloom E, Lee HJ (2016) Valproic acid exposure during early postnatal gliogenesis leads to autistic-like behaviors in rats. Clin Psychopharmacol Neurosci, 14:338.
• Moore S, Turnpenny P, Quinn A, Glover S, Lloyd D, Montgomery T, Dean J (2000) A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet, 37:489-497.
• Morais LH, Schreiber HL, Mazmanian SK (2021) The gut microbiota–brain axis in behaviour and brain disorders. Nat Rev Microbiol , 19:241-255.
• Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J et al. (2010) Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry , 68:368-376.
• Mottron L (2021) A radical change in our autism research strategy is needed: Back to prototypes. Autism Res, 14:2213-2220.
• Nagai J, Yu X, Papouin T, Cheon E, Freeman MR, Monk KR et al. (2021) Behaviorally consequential astrocytic regulation of neural circuits. Neuron, 109:576-596.
• Nanson J (1992) Autism in fetal alcohol syndrome: a report of six cases. Alcohol Clin Exp Res, 16:558-565.
• Nishiyama A, Yang Z, Butt A (2005) Astrocytes and NG2‐glia: what's in a name? J Anat, 207:687-693.
• Noh HS, Kang SS, Kim DW, Kim YH, Park CH, Han JY et al. (2005) Ketogenic diet increases calbindin-D28k in the hippocampi of male ICR mice with kainic acid seizures. Epilepsy Res, 65:153-159.
• Onore C, Careaga M, Ashwood P (2012) The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun, 26:383-392.
• Palmen SJ, van Engeland H, Hof PR, Schmitz C (2004) Neuropathological findings in autism. Brain Sci, 127:2572-2583.
• Park K, Lee SJ (2020) Deciphering the star codings: astrocyte manipulation alters mouse behavior. Exp Mol Med, 52:1028-1038.
• Pastural É, Ritchie S, Lu Y, Jin W, Kavianpour A, Su-Myat KK et al. (2009) Novel plasma phospholipid biomarkers of autism: mitochondrial dysfunction as a putative causative mechanism. Prostaglandins Leukot Essent Fatty Acids, 81:253-264.
• Patel S, Dale RC, Rose D, Heath B, Nordahl CW, Rogers S et al. (2020) Maternal immune conditions are increased in males with autism spectrum disorders and are associated with behavioural and emotional but not cognitive co-morbidity. Transl Psychiatry, 10:265.
• Pavăl D (2017) A dopamine hypothesis of autism spectrum disorder. Dev Neurosci, 39:355-360.
• Pekny, M., Wilhelmsson, U., Bogestål, Y. R. Ve Pekna, M. (2007). The role of astrocytes and complement system in neural plasticity. Int Rev Neurobiol, 82:95-111.
• Perry VH, Teeling J (2013) Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol, 35:601-612.
• Rahn KA, Slusher BS, Kaplin AI (2012) Glutamate in CNS neurodegeneration and cognition and its regulation by GCPII inhibition. Curr Med Chem, 19:1335-1345.
• Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S et al. (2006) Advancing paternal age and autism. Arch Gen Psychiatry, 63:1026-1032.
• Rodriguez JI, Kern JK (2011) Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol, 7:205-213.
• Schmitz C, Rezaie P (2008) The neuropathology of autism: where do we stand? Neuropathol Appl Neurobiol, 34:4-11.
• Schmitz T, Chew LJ (2008) Cytokines and myelination in the central nervous system. Sci World J, 8:1119-1147.
• Schumann CM, Amaral DG (2006) Stereological analysis of amygdala neuron number in autism. J Neurosci, 26:7674-7679.
• Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA et al. (2019) Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron, 101:246-259.e246.
• Smith SE, Zhou YD, Zhang G, Jin Z, Stoppel DC, Anderson MP (2011) Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci Transl Med, 3:103ra197-103ra197.
• Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci, 16:249-263.
• Stallcup WB (1981) The NG2 antigen, a putative lineage marker: immunofluorescent localization in primary cultures of rat brain. Dev Biol, 83:154-165.
• Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K et al. (2013) Microglial activation in young adults with autism spectrum disorder. JAMA, 70:49-58.
• Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A et al. (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron, 83:1131-1143.
• Tetreault NA, Hakeem AY, Jiang S, Williams BA, Allman E, Wold BJ et al. (2012) Microglia in the cerebral cortex in autism. J Autism Dev Disord, 42:2569-2584.
• Tremblay MÈ, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol, 8:e1000527.
• Tsai LY (2014) Impact of DSM-5 on epidemiology of Autism Spectrum Disorder. Res Autism Spectr Disord, 8:1454-1470.
• van Kooten IA, Palmen SJ, von Cappeln P, Steinbusch HW, Korr H, Heinsen H et al. (2008) Neurons in the fusiform gyrus are fewer and smaller in autism. Brain, 131:987-999.
• Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol, 57:67-81.
• Varghese M, Keshav N, Jacot-Descombes S, Warda T, Wicinski B, Dickstein DL et al. (2017) Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol, 134:537-566.
• Verkhratsky A, Butt A (2013) Glial Physiology and Pathophysiology. Oxford, UK, Wiley.
• Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev, 98:239-389.
• Virchow R (2020) Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. Glasgow, UK, Good Press.
• Wang Q, Kong Y, Wu DY, Liu JH, Jie W, You QL et al. (2021) Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice. Nat Commun, 12:3321.
• Waterhouse L, Morris R, Allen D, Dunn M, Fein D, Feinstein C, Rapin I, Wing L (1996) Diagnosis and classification in autism. J Autism Dev Disord, 26:59-86.
• Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT et al. (2011) IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation, 8:52.
• Weinhard L, Di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U et al. (2018) Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun, 9:1228.
• Williamson SJ, Yooseph S (2012) From bacterial to microbial ecosystems (metagenomics). Methods Mol Biol, 804:35-55..
• Wong RS (2022) Neuroinflammation in autism spectrum disorders: potential target for mesenchymal stem cell-based therapy. Egypt J Neurol Psychiatr Neurosurg, 58:91.
• Wu S, Wu F, Ding Y, Hou, Bi J, Zhang Z (2017) Advanced parental age and autism risk in children: a systematic review and meta‐analysis. Acta Psychiatr Scand, 135:29-41.
• Yousef AM, Roshdy EH, Abdel Fattah NR, Said RM, Atia MM, Hafez EM et al. (2021) Prevalence and risk factors of autism spectrum disorders in preschool children in Sharkia, Egypt: A community-based study. Middle East Curr Psychiatry, 28:36.
• Yu Y, Zhao F (2021) Microbiota-gut-brain axis in autism spectrum disorder. J Genet Genomics 48:755-762.
• Zeidán-Chuliá F, Salmina AB, Malinovskaya NA, Noda M, Verkhratsky A, Moreira JCF (2014) The glial perspective of autism spectrum disorders. Neurosci Biobehav Rev, 38:160-172.
• Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F et al. (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 17:400-406.
• Zhou Y, Danbolt NC (2014) Glutamate as a neurotransmitter in the healthy brain. J Neural Transm, 121:799-817.
• Zikopoulos B, Barbas H (2010) Changes in prefrontal axons may disrupt the network in autism. J Neurosci, 30:14595-14609.
• Zürcher N, Loggia M, Mullett J, Tseng C, Bhanot A, Richey L et al. (2021) [11C] PBR28 MR–PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder. Mol Psychiatry, 26:1659-1669.