Modelling the Interplay Between Neuron-Glia Cell Dysfunction and Glial
Therapy in Autism Spectrum Disorder

Aziz      Unnisa; Nigel   H.   Greig; Mohammad   Amjad   Kamal
doi:10.2174/1570159X21666221221142743
Abstract

Autism spectrum disorder (ASD) is a complicated, interpersonally defined, static condition of the underdeveloped brain. Although the aetiology of autism remains unclear, disturbance of neuronglia interactions has lately been proposed as a significant event in the pathophysiology of ASD. In recent years, the contribution of glial cells to autism has been overlooked. In addition to neurons, glial cells play an essential role in mental activities, and a new strategy that emphasises neuron-glia interactions should be applied. Disturbance of neuron-glia connections has lately been proposed as a significant event in the pathophysiology of ASD because aberrant neuronal network formation and dysfunctional neurotransmission are fundamental to the pathology of the condition. In ASD, neuron and glial cell number changes cause brain circuits to malfunction and impact behaviour. A study revealed that reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Recent discoveries also suggest that dysfunction or changes in the ability of microglia to carry out physiological and defensive functions (such as failure in synaptic elimination or aberrant microglial activation) may be crucial for developing brain diseases, especially autism. The cerebellum, white matter, and cortical regions of autistic patients showed significant microglial activation. Reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Replacement of defective glial cells (Cell-replacement treatment), glial progenitor cell-based therapy, and medication therapy (inhibition of microglia activation) are all utilised to treat glial dysfunction. This review discusses the role of glial cells in ASD and the various potential approaches to treating glial cell dysfunction.
« Previous Next »
Graphical Abstract

[1]
Scuderi, C.; Verkhratsky, A. The role of neuroglia in autism spectrum disorders. Prog. Mol. Biol. Transl. Sci.,  2020, 173, 301-330.
 [http://dx.doi.org/10.1016/bs.pmbts.2020.04.011] [PMID: 32711814]

[2]
Kato, T.A.; Watabe, M.; Kanba, S. Neuron-glia interaction as a possible glue to translate the mind-brain gap: A novel multi-dimensional approach toward psychology and psychiatry. Front. Psychiatry,  2013, 4, 139.
 [http://dx.doi.org/10.3389/fpsyt.2013.00139] [PMID: 24155727]

[3]
Fields, R.D.; Burnstock, G. Purinergic signalling in neuron–glia interactions. Nat. Rev. Neurosci.,  2006, 7(6), 423-436.
 [http://dx.doi.org/10.1038/nrn1928] [PMID: 16715052]

[4]
Stogsdill, J.A.; Eroglu, C. The interplay between neurons and glia in synapse development and plasticity. Curr. Opin. Neurobiol.,  2017, 42, 1-8.
 [http://dx.doi.org/10.1016/j.conb.2016.09.016] [PMID: 27788368]

[5]
Gomes, F.C.A.; Spohr, T.C.L.S.; Martinez, R.; Moura Neto, V. Cross-talk between neurons and glia: Highlights on soluble factors. Braz. J. Med. Biol. Res.,  2001, 34(5), 611-620.
 [http://dx.doi.org/10.1590/S0100-879X2001000500008] [PMID: 11323747]

[6]
Cserép, C.; Pósfai, B.; Dénes, Á. Shaping neuronal fate: Functional heterogeneity of direct microglia-neuron interactions. Neuron,  2021, 109(2), 222-240.
 [http://dx.doi.org/10.1016/j.neuron.2020.11.007] [PMID: 33271068]

[7]
Pósfai, B.; Cserép, C.; Orsolits, B.; Dénes, Á. New insights into microglia–neuron interactions: A neuron’s perspective. Neuroscience,  2019, 405, 103-117.
 [http://dx.doi.org/10.1016/j.neuroscience.2018.04.046] [PMID: 29753862]

[8]
Wieghofer, P.; Knobeloch, K.P.; Prinz, M. Genetic targeting of microglia. Glia,  2015, 63(1), 1-22.
 [http://dx.doi.org/10.1002/glia.22727] [PMID: 25132502]

[9]
Goldmann, T.; Wieghofer, P.; Müller, P.F.; Wolf, Y.; Varol, D.; Yona, S.; Brendecke, S.M.; Kierdorf, K.; Staszewski, O.; Datta, M.; Luedde, T.; Heikenwalder, M.; Jung, S.; Prinz, M. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat. Neurosci.,  2013, 16(11), 1618-1626.
 [http://dx.doi.org/10.1038/nn.3531] [PMID: 24077561]

[10]
Dzyubenko, E.; Gottschling, C.; Faissner, A. Neuron-glia interactions in neural plasticity: Contributions of neural extracellular matrix and perineuronal nets. Neural Plast.,  2016, 2016, 1-14.
 [http://dx.doi.org/10.1155/2016/5214961] [PMID: 26881114]

[11]
Duncan, G.J.; Simkins, T.J.; Emery, B. Neuron-oligodendrocyte interactions in the structure and integrity of axons. Front. Cell Dev. Biol.,  2021, 9, 653101.
 [http://dx.doi.org/10.3389/fcell.2021.653101] [PMID: 33763430]

[12]
Gritti, A.; Bonfanti, L. Neuronal–glial interactions in central nervous system neurogenesis: The neural stem cell perspective. Neuron Glia Biol.,  2007, 3(4), 309-323.
 [http://dx.doi.org/10.1017/S1740925X0800001X] [PMID: 18634563]

[13]
Shimizu, T.; Osanai, Y.; Ikenaka, K. Oligodendrocyte–neuron interactions: Impact on myelination and brain function. Neurochem. Res.,  2018, 43(1), 190-194.
 [http://dx.doi.org/10.1007/s11064-017-2387-5] [PMID: 28918515]

[14]
Afridi, R.; Kim, J.H.; Rahman, M.H.; Suk, K. Metabolic regulation of glial phenotypes: Implications in neuron–glia interactions and neurological disorders. Front. Cell. Neurosci.,  2020, 14, 20.
 [http://dx.doi.org/10.3389/fncel.2020.00020] [PMID: 32116564]

[15]
Salmina, A.B. Neuron-glia interactions as therapeutic targets in neurodegeneration. J. Alzheimers Dis.,  2009, 16(3), 485-502.
 [http://dx.doi.org/10.3233/JAD-2009-0988] [PMID: 19276541]

[16]
Abdelli, L.S.; Samsam, A.; Naser, S.A. Propionic acid induces gliosis and neuro-inflammation through modulation of PTEN/AKT pathway in autism spectrum disorder. Sci. Rep.,  2019, 9(1), 8824.
 [http://dx.doi.org/10.1038/s41598-019-45348-z] [PMID: 31217543]

[17]
Laming, P.R.; Kimelberg, H.; Robinson, S.; Salm, A.; Hawrylak, N.; Müller, C.; Roots, B.; Ng, K. Neuronal–glial interactions and behaviour. Neurosci. Biobehav. Rev.,  2000, 24(3), 295-340.
 [http://dx.doi.org/10.1016/S0149-7634(99)00080-9] [PMID: 10781693]

[18]
Chen, J.A.; Peñagarikano, O.; Belgard, T.G.; Swarup, V.; Geschwind, D.H. The emerging picture of autism spectrum disorder: Genetics and pathology. Annu. Rev. Pathol.,  2015, 10(1), 111-144.
 [http://dx.doi.org/10.1146/annurev-pathol-012414-040405] [PMID: 25621659]

[19]
Benarroch, E.E. Neuron-astrocyte interactions: Partnership for normal function and disease in the central nervous system. Mayo Clin. Proc.,  2005, 80(10), 1326-1338.
 [http://dx.doi.org/10.4065/80.10.1326] [PMID: 16212146]

[20]
Tsai, P.T.; Hull, C.; Chu, Y.; Greene-Colozzi, E.; Sadowski, A.R.; Leech, J.M.; Steinberg, J.; Crawley, J.N.; Regehr, W.G.; Sahin, M. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature,  2012, 488(7413), 647-651.
 [http://dx.doi.org/10.1038/nature11310] [PMID: 22763451]

[21]
Gogolla, N.; Takesian, A.E.; Feng, G.; Fagiolini, M.; Hensch, T.K. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron,  2014, 83(4), 894-905.
 [http://dx.doi.org/10.1016/j.neuron.2014.06.033] [PMID: 25088363]

[22]
Hammer, M.; Krueger-Burg, D.; Tuffy, L.P.; Cooper, B.H.; Taschenberger, H.; Goswami, S.P.; Ehrenreich, H.; Jonas, P.; Varoqueaux, F.; Rhee, J.S.; Brose, N. Perturbed hippocampal synaptic inhibition and γ-oscillations in a neuroligin-4 knockout mouse model of autism. Cell Rep.,  2015, 13(3), 516-523.
 [http://dx.doi.org/10.1016/j.celrep.2015.09.011] [PMID: 26456829]

[23]
Chao, H.T.; Chen, H.; Samaco, R.C.; Xue, M.; Chahrour, M.; Yoo, J.; Neul, J.L.; Gong, S.; Lu, H.C.; Heintz, N.; Ekker, M.; Rubenstein, J.L.R.; Noebels, J.L.; Rosenmund, C.; Zoghbi, H.Y. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature,  2010, 468(7321), 263-269.
 [http://dx.doi.org/10.1038/nature09582] [PMID: 21068835]

[24]
Sloan, S.A.; Barres, B.A. Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders. Curr. Opin. Neurobiol.,  2014, 27, 75-81.
 [http://dx.doi.org/10.1016/j.conb.2014.03.005] [PMID: 24694749]

[25]
Busch, R.M.; Srivastava, S.; Hogue, O.; Frazier, T.W.; Klaas, P.; Hardan, A.; Martinez-Agosto, J.A.; Sahin, M.; Eng, C. Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Transl. Psychiatry,  2019, 9(1), 253.
 [http://dx.doi.org/10.1038/s41398-019-0588-1] [PMID: 31594918]

[26]
Gumusoglu, S.B.; Fine, R.S.; Murray, S.J.; Bittle, J.L.; Stevens, H.E. The role of IL-6 in neurodevelopment after prenatal stress. Brain Behav. Immun.,  2017, 65, 274-283.
 [http://dx.doi.org/10.1016/j.bbi.2017.05.015] [PMID: 28546058]

[27]
Goines, P.E.; Croen, L.A.; Braunschweig, D.; Yoshida, C.K.; Grether, J.; Hansen, R.; Kharrazi, M.; Ashwood, P.; Van de Water, J. Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study. Mol. Autism,  2011, 2(1), 13.
 [http://dx.doi.org/10.1186/2040-2392-2-13] [PMID: 21810230]

[28]
Hsiao, E.Y.; McBride, S.W.; Hsien, S.; Sharon, G.; Hyde, E.R.; McCue, T.; Codelli, J.A.; Chow, J.; Reisman, S.E.; Petrosino, J.F.; Patterson, P.H.; Mazmanian, S.K. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell,  2013, 155(7), 1451-1463.
 [http://dx.doi.org/10.1016/j.cell.2013.11.024] [PMID: 24315484]

[29]
Choi, G.B.; Yim, Y.S.; Wong, H.; Kim, S.; Kim, H.; Kim, S.V.; Hoeffer, C.A.; Littman, D.R.; Huh, J.R. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science,  2016, 351(6276), 933-939.
 [http://dx.doi.org/10.1126/science.aad0314] [PMID: 26822608]

[30]
Croen, L.A.; Grether, J.K.; Yoshida, C.K.; Odouli, R.; Van de Water, J. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: A case-control study. Arch. Pediatr. Adolesc. Med.,  2005, 159(2), 151-157.
 [http://dx.doi.org/10.1001/archpedi.159.2.151] [PMID: 15699309]

[31]
Horváth, G.; Otrokocsi, L.; Bekő, K.; Baranyi, M.; Kittel, Á.; Antonio Fritz-Ruenes, P.; Sperlágh, B. P2X7 receptors drive poly(I:C) induced autism-like behavior in mice. J. Neurosci.,  2019, 39(13), 1895-18.
 [http://dx.doi.org/10.1523/JNEUROSCI.1895-18.2019] [PMID: 30683682]

[32]
Ibrahim, A.M.; Pottoo, F.H.; Dahiya, E.S.; Khan, F.A.; Kumar, J.B.S. Neuron‐glia interactions: Molecular basis of alzheimer’s disease and applications of neuroproteomics. Eur. J. Neurosci.,  2020, 52(2), 2931-2943.
 [http://dx.doi.org/10.1111/ejn.14838] [PMID: 32463535]

[33]
Muhle, R.; Trentacoste, S.V.; Rapin, I. The genetics of autism. Pediatrics,  2004, 113(5), e472-e486.
 [http://dx.doi.org/10.1542/peds.113.5.e472] [PMID: 15121991]

[34]
Kim, Y.S.; Choi, J.; Yoon, B.E. Neuron-glia interactions in neurodevelopmental disorders. Cells,  2020, 9(10), 2176.
 [http://dx.doi.org/10.3390/cells9102176] [PMID: 32992620]

[35]
Petrelli, F.; Pucci, L.; Bezzi, P. Astrocytes and microglia and their potential link with autism spectrum disorders. Front. Cell. Neurosci.,  2016, 10, 21.
 [http://dx.doi.org/10.3389/fncel.2016.00021] [PMID: 26903806]

[36]
Öngür, D.; Jensen, J.E.; Prescot, A.P.; Stork, C.; Lundy, M.; Cohen, B.M.; Renshaw, P.F. Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol. Psychiatry,  2008, 64(8), 718-726.
 [http://dx.doi.org/10.1016/j.biopsych.2008.05.014] [PMID: 18602089]

[37]
Pardo, C.A.; Vargas, D.L.; Zimmerman, A.W. Immunity, neuroglia and neuroinflammation in autism. Int. Rev. Psychiatry,  2005, 17(6), 485-495.
 [http://dx.doi.org/10.1080/02646830500381930] [PMID: 16401547]

[38]
Takano, T. Role of microglia in autism: Recent advances. Dev. Neurosci.,  2015, 37(3), 195-202.
 [http://dx.doi.org/10.1159/000398791] [PMID: 25998072]

[39]
Bronzuoli, M.R.; Facchinetti, R.; Ingrassia, D.; Sarvadio, M.; Schiavi, S.; Steardo, L.; Verkhratsky, A.; Trezza, V.; Scuderi, C. Neuroglia in the autistic brain: Evidence from a preclinical model. Mol. Autism,  2018, 9(1), 66.
 [http://dx.doi.org/10.1186/s13229-018-0254-0] [PMID: 30603062]

[40]
Vargas, D.L.; Nascimbene, C.; Krishnan, C.; Zimmerman, A.W.; Pardo, C.A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol.,  2005, 57(1), 67-81.
 [http://dx.doi.org/10.1002/ana.20315] [PMID: 15546155]

[41]
Cresto, N.; Pillet, L.E.; Billuart, P.; Rouach, N. Do astrocytes play a role in intellectual disabilities? Trends Neurosci.,  2019, 42(8), 518-527.
 [http://dx.doi.org/10.1016/j.tins.2019.05.011] [PMID: 31300246]

[42]
Muotri, A.R. The human model: Changing focus on autism research. Biol. Psychiatry,  2016, 79(8), 642-649.
 [http://dx.doi.org/10.1016/j.biopsych.2015.03.012] [PMID: 25861701]

[43]
Voineagu, I.; Wang, X.; Johnston, P.; Lowe, J.K.; Tian, Y.; Horvath, S.; Mill, J.; Cantor, R.M.; Blencowe, B.J.; Geschwind, D.H. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature,  2011, 474(7351), 380-384.
 [http://dx.doi.org/10.1038/nature10110] [PMID: 21614001]

[44]
Edmonson, C.; Ziats, M.N.; Rennert, O.M. Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Mol. Autism,  2014, 5(1), 3.
 [http://dx.doi.org/10.1186/2040-2392-5-3] [PMID: 24410870]

[45]
Kaminsky, N.; Bihari, O.; Kanner, S.; Barzilai, A. Connecting malfunctioning glial cells and brain degenerative disorders. Genomics Proteomics Bioinformatics,  2016, 14(3), 155-165.
 [http://dx.doi.org/10.1016/j.gpb.2016.04.003] [PMID: 27245308]

[46]
Falcone, C.; Mevises, N.Y.; Hong, T.; Dufour, B.; Chen, X.; Noctor, S.C.; Martínez Cerdeño, V. Neuronal and glial cell number is altered in a cortical layer-specific manner in autism. Autism,  2021, 25(8), 2238-2253.
 [http://dx.doi.org/10.1177/13623613211014408] [PMID: 34107793]

[47]
Osorio, M.J.; Goldman, S.A. Glial progenitor cell-based treatment of the childhood leukodystrophies. Exp Neurol,  2016, 283(Pt B), 476-488.
 [http://dx.doi.org/10.1016/j.expneurol.2016.05.010]

[48]
Lyons, A.; Downer, E.J.; Crotty, S.; Nolan, Y.M.; Mills, K.H.G.; Lynch, M.A. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: A role for IL-4. J. Neurosci.,  2007, 27(31), 8309-8313.
 [http://dx.doi.org/10.1523/JNEUROSCI.1781-07.2007] [PMID: 17670977]

[49]
Stevenson, R.; Samokhina, E.; Rossetti, I.; Morley, J.W.; Buskila, Y. Neuromodulation of glial function during neurodegeneration. Front. Cell. Neurosci.,  2020, 14, 278.
 [http://dx.doi.org/10.3389/fncel.2020.00278] [PMID: 32973460]

[50]
Rodriguez, J.I.; Kern, J.K. Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol.,  2011, 7(2-4), 205-213.
 [http://dx.doi.org/10.1017/S1740925X12000142] [PMID: 22874006]

[51]
Zeidán-Chuliá, F.; Salmina, A.B.; Malinovskaya, N.A.; Noda, M.; Verkhratsky, A.; Moreira, J.C.F. The glial perspective of autism spectrum disorders. Neurosci. Biobehav. Rev.,  2014, 38, 160-172.
 [http://dx.doi.org/10.1016/j.neubiorev.2013.11.008] [PMID: 24300694]

[52]
Xu, Z.X.; Kim, G.H.; Tan, J.W.; Riso, A.E.; Sun, Y.; Xu, E.Y.; Liao, G.Y.; Xu, H.; Lee, S.H.; Do, N.Y.; Lee, C.H.; Clipperton-Allen, A.E.; Kwon, S.; Page, D.T.; Lee, K.J.; Xu, B. Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations. Nat. Commun.,  2020, 11(1), 1797.
 [http://dx.doi.org/10.1038/s41467-020-15530-3] [PMID: 32286273]

[53]
Molofsky, A.V.; Krenick, R.; Ullian, E.; Tsai, H.; Deneen, B.; Richardson, W.D.; Barres, B.A.; Rowitch, D.H. Astrocytes and disease: A neurodevelopmental perspective. Genes Dev.,  2012, 26(9), 891-907.
 [http://dx.doi.org/10.1101/gad.188326.112] [PMID: 22549954]

[54]
Wang, Q.; Kong, Y.; Wu, D.Y.; Liu, J.H.; Jie, W.; You, Q.L.; Huang, L.; Hu, J.; Chu, H.D.; Gao, F.; Hu, N.Y.; Luo, Z.C.; Li, X.W.; Li, S.J.; Wu, Z.F.; Li, Y.L.; Yang, J.M.; Gao, T.M. Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice. Nat. Commun.,  2021, 12(1), 3321.
 [http://dx.doi.org/10.1038/s41467-021-23843-0] [PMID: 34059669]

[55]
Russo, F.B.; Freitas, B.C.; Pignatari, G.C.; Fernandes, I.R.; Sebat, J.; Muotri, A.R.; Beltrão-Braga, P.C.B. Modeling the interplay between neurons and astrocytes in autism using human induced pluripotent stem cells. Biol. Psychiatry,  2018, 83(7), 569-578.
 [http://dx.doi.org/10.1016/j.biopsych.2017.09.021] [PMID: 29129319]

[56]
Benedetto, B.; Rupprecht, R. Targeting glia cells: Novel perspectives for the treatment of neuropsychiatric diseases. Curr. Neuropharmacol.,  2013, 11(2), 171-185.
 [http://dx.doi.org/10.2174/1570159X11311020004] [PMID: 23997752]

[57]
Li, Y.J.; Zhang, X.; Li, Y.M. Antineuroinflammatory therapy: Potential treatment for autism spectrum disorder by inhibiting glial activation and restoring synaptic function. CNS Spectr.,  2020, 25(4), 493-501.
 [http://dx.doi.org/10.1017/S1092852919001603] [PMID: 31659946]

[58]
Almad, A.A.; Maragakis, N.J. Glia: An emerging target for neurological disease therapy. Stem Cell Res. Ther.,  2012, 3(5), 37.
 [http://dx.doi.org/10.1186/scrt128] [PMID: 23021042]

[59]
Davies, S.J.A.; Shih, C.H.; Noble, M.; Mayer-Proschel, M.; Davies, J.E.; Proschel, C. Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS One,  2011, 6(3), e17328.
 [http://dx.doi.org/10.1371/journal.pone.0017328] [PMID: 21407803]

[60]
Gleichman, A.J.; Carmichael, S.T. Astrocytic therapies for neuronal repair in stroke. Neurosci. Lett.,  2014, 565, 47-52.
 [http://dx.doi.org/10.1016/j.neulet.2013.10.055] [PMID: 24184876]

[61]
Goldman, S.A. Progenitor cell-based treatment of glial disease. Prog. Brain Res; , 2017, p. 231, 165-189.
 [http://dx.doi.org/10.1016/bs.pbr.2017.02.010] [PMID: 28554396]

[62]
Roy, N.S.; Wang, S.; Harrison-Restelli, C.; Benraiss, A.; Fraser, R.A.R.; Gravel, M.; Braun, P.E.; Goldman, S.A. Identification, isolation, and promoter-defined separation of mitotic oligodendrocyte progenitor cells from the adult human subcortical white matter. J. Neurosci.,  1999, 19(22), 9986-9995.
 [http://dx.doi.org/10.1523/JNEUROSCI.19-22-09986.1999] [PMID: 10559406]

[63]
Goldman, S.A.; Nedergaard, M.; Windrem, M.S. Glial progenitor cell-based treatment and modeling of neurological disease. Science,  2012, 338(6106), 491-495.
 [http://dx.doi.org/10.1126/science.1218071] [PMID: 23112326]

[64]
Goldman, S.A.; Mariani, J.N.; Madsen, P.M. Glial progenitor cell-based repair of the dysmyelinated brain: Progression to the clinic. Semin. Cell Dev. Biol.,  2021, 116, 62-70.
 [http://dx.doi.org/10.1016/j.semcdb.2020.12.004] [PMID: 33414060]

[65]
Sim, F.J.; Windrem, M.S.; Goldman, S.A. Fate determination of adult human glial progenitor cells. Neuron Glia Biol.,  2009, 5(3-4), 45-55.
 [http://dx.doi.org/10.1017/S1740925X09990317] [PMID: 19807941]

[66]
Keyoung, H.M.; Goldman, S.A. Glial progenitor-based repair of demyelinating neurological diseases. Neurosurg. Clin. N. Am.,  2007, 18(1), 93-104. [x.
 [http://dx.doi.org/10.1016/j.nec.2006.10.009] [PMID: 17244557]

[67]
Vélez-Fort, M.; Audinat, E.; Angulo, M.C. Central role of GABA in neuron-glia interactions. Neuroscientist,  2012, 18(3), 237-250.
 [http://dx.doi.org/10.1177/1073858411403317] [PMID: 21609943]

[68]
Wang, Q.; Hong, P.; Gao, H.; Chen, Y.; Yang, Q.; Jiang, M.; Li, H. An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain. Sci. Rep.,  2016, 6(1), 19003.
 [http://dx.doi.org/10.1038/srep19003] [PMID: 26750620]

[69]
Giacomoni, J.; Bruzelius, A.; Stamouli, C.A.; Rylander Ottosson, D. Direct conversion of human stem cell-derived glial progenitor cells into GABAergic interneurons. Cells,  2020, 9(11), 2451.
 [http://dx.doi.org/10.3390/cells9112451] [PMID: 33182669]

[70]
Sun, A.X.; Yuan, Q.; Tan, S.; Xiao, Y.; Wang, D.; Khoo, A.T.T.; Sani, L.; Tran, H.D.; Kim, P.; Chiew, Y.S.; Lee, K.J.; Yen, Y.C.; Ng, H.H.; Lim, B.; Je, H.S. Direct induction and functional maturation of forebrain GABAergic neurons from human pluripotent stem cells. Cell Rep.,  2016, 16(7), 1942-1953.
 [http://dx.doi.org/10.1016/j.celrep.2016.07.035] [PMID: 27498872]

[71]
Benarroch, E.E. Microglia: Multiple roles in surveillance, circuit shaping, and response to injury. Neurology,  2013, 81(12), 1079-1088.
 [http://dx.doi.org/10.1212/WNL.0b013e3182a4a577] [PMID: 23946308]

[72]
Bachiller, S.; Jiménez-Ferrer, I.; Paulus, A.; Yang, Y.; Swanberg, M.; Deierborg, T. What can we do for better understanding of microglial phenotype in neuronal disorder? Front. Cell. Neurosci.,  2018, 12, 488.
 [http://dx.doi.org/10.3389/fncel.2018.00488] [PMID: 30618635]

[73]
Zhang, Y.; Xie, Y.; Cheng, Z.; Zhang, Y.; Wang, W.; Guo, B.; Wu, S. Mechanism of action and therapeutic targeting of microglia in autism spectrum disorder. Adv. Neurol.,  2022, 1(3), 167.

[74]
Kalkman, H.; Feuerbach, D. Microglia M2A polarization as potential link between food allergy and autism spectrum disorders. Pharmaceuticals (Basel),  2017, 10(4), 95.
 [http://dx.doi.org/10.3390/ph10040095] [PMID: 29232822]

[75]
Harry, G.J.; Kraft, A.D. Neuroinflammation and microglia: Considerations and approaches for neurotoxicity assessment. Expert Opin. Drug Metab. Toxicol.,  2008, 4(10), 1265-1277.
 [http://dx.doi.org/10.1517/17425255.4.10.1265] [PMID: 18798697]

[76]
Nayak, D.; Roth, T.L.; McGavern, D.B. Microglia development and function. Annu. Rev. Immunol.,  2014, 32(1), 367-402.
 [http://dx.doi.org/10.1146/annurev-immunol-032713-120240] [PMID: 24471431]

[77]
Hellwig, S.; Heinrich, A.; Biber, K. The brain’s best friend: Microglial neurotoxicity revisited. Front. Cell. Neurosci.,  2013, 7, 71.
 [http://dx.doi.org/10.3389/fncel.2013.00071] [PMID: 23734099]

[78]
Liberman, A.C.; Trias, E.; da Silva Chagas, L.; Trindade, P.; dos Santos Pereira, M.; Refojo, D.; Hedin-Pereira, C.; Serfaty, C.A. Neuroimmune and inflammatory signals in complex disorders of the central nervous system. Neuroimmunomodulation,  2018, 25(5-6), 246-270.
 [http://dx.doi.org/10.1159/000494761] [PMID: 30517945]

[79]
Pangrazzi, L.; Balasco, L.; Bozzi, Y. Oxidative stress and immune system dysfunction in autism spectrum disorders. Int. J. Mol. Sci.,  2020, 21(9), 3293.
 [http://dx.doi.org/10.3390/ijms21093293] [PMID: 32384730]

[80]
Jurga, A.M.; Paleczna, M.; Kuter, K.Z. Overview of general and discriminating markers of differential microglia phenotypes. Front. Cell. Neurosci.,  2020, 14, 198.
 [http://dx.doi.org/10.3389/fncel.2020.00198] [PMID: 32848611]

[81]
Fan, J.; Saft, M.; Sadanandan, N.; Gonzales-Portillo, B.; Park, Y.J.; Sanberg, P.R.; Borlongan, C.V.; Luo, Y. LncRNAs stand as potent biomarkers and therapeutic targets for stroke. Front. Aging Neurosci.,  2020, 12, 594571.
 [http://dx.doi.org/10.3389/fnagi.2020.594571] [PMID: 33192490]

[82]
Zhang, X.; Zhu, X.L.; Ji, B.Y.; Cao, X.; Yu, L.J.; Zhang, Y.; Bao, X.Y.; Xu, Y.; Jin, J.L. LncRNA-1810034E14Rik reduces microglia activation in experimental ischemic stroke. J. Neuroinflammation,  2019, 16(1), 75.
 [http://dx.doi.org/10.1186/s12974-019-1464-x] [PMID: 30961627]

[83]
Davoli-Ferreira, M.; Thomson, C.A.; McCoy, K.D. Microbiota and microglia interactions in ASD. Front. Immunol.,  2021, 12, 676255.
 [http://dx.doi.org/10.3389/fimmu.2021.676255] [PMID: 34113350]

[84]
Traetta, M.E.; Codagnone, M.G.; Uccelli, N.A.; Ramos, A.J.; Zárate, S.; Reinés, A. Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: Evidence of neuronal priming during early development in autism spectrum disorders. Mol. Autism,  2021, 12(1), 23.
 [http://dx.doi.org/10.1186/s13229-021-00428-8] [PMID: 33676530]

[85]
Galvani, G.; Mottolese, N.; Gennaccaro, L.; Loi, M.; Medici, G.; Tassinari, M.; Fuchs, C.; Ciani, E.; Trazzi, S. Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder. J. Neuroinflammation,  2021, 18(1), 155.
 [http://dx.doi.org/10.1186/s12974-021-02204-0] [PMID: 34238328]

[86]
Victor, T.R.; Tsirka, S.E. Microglial contributions to aberrant neurogenesis and pathophysiology of epilepsy. Neuroimmunol. Neuroinflamm.,  2020, 2020, 234-247.
 [http://dx.doi.org/10.20517/2347-8659.2020.02] [PMID: 33154976]

[87]
Kielian, T.; Esen, N.; Liu, S.; Phulwani, N.K.; Syed, M.M.; Phillips, N.; Nishina, K.; Cheung, A.L.; Schwartzman, J.D.; Ruhe, J.J. Minocycline modulates neuroinflammation independently of its antimicrobial activity in Staphylococcus aureus-induced brain abscess. Am. J. Pathol.,  2007, 171(4), 1199-1214.
 [http://dx.doi.org/10.2353/ajpath.2007.070231] [PMID: 17717149]

[88]
Wang, A.; Yu, A.; Lau, L.; Lee, C.; Wu, L.; Zhu, X.; Tso, M. Minocycline inhibits LPS-induced retinal microglia activation. Neurochem. Int.,  2005, 47(1-2), 152-158.
 [http://dx.doi.org/10.1016/j.neuint.2005.04.018] [PMID: 15904993]

[89]
Plane, J.M.; Shen, Y.; Pleasure, D.E. Prospects for minocycline neuroprotection. Neurol. Rev.,  2010, 67(12), 1442-1448.

[90]
Edan, R.A.; Luqmani, Y.A.; Masocha, W.; Block, M.L. COL-3, a chemically modified tetracycline, inhibits lipopolysaccharide-induced microglia activation and cytokine expression in the brain. PLoS One,  2013, 8(2), e57827.
 [http://dx.doi.org/10.1371/journal.pone.0057827]

[91]
Henry, C.J.; Huang, Y.; Wynne, A.; Hanke, M.; Himler, J.; Bailey, M.T.; Sheridan, J.F.; Godbout, J.P. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J. Neuroinflammation,  2008, 5(1), 15.
 [http://dx.doi.org/10.1186/1742-2094-5-15] [PMID: 18477398]

[92]
Marchezan, J.; Winkler dos Santos, E.G.A.; Deckmann, I.; Riesgo, R.S. Immunological dysfunction in autism spectrum disorder: A potential target for therapy. Neuroimmunomodulation,  2018, 25(5-6), 300-319.
 [http://dx.doi.org/10.1159/000492225] [PMID: 30184549]

[93]
Duque, E.A.; Munhoz, C.D. The pro-inflammatory effects of glucocorticoids in the brain. Front. Endocrinol. (Lausanne),  2016, 7, 78.
 [http://dx.doi.org/10.3389/fendo.2016.00078] [PMID: 27445981]

[94]
Radtke, F.A.; Chapman, G.; Hall, J.; Yasi, A.S. Modulating neuroinflammation to treat neuropsychiatric disorders. BioMed Res. Int.,  2017, 5071786.
 [http://dx.doi.org/10.1155/2017/5071786]

[95]
Nasib, L.G.; Sommer, I.E. Winter - van Rossum, I.; de Vries, J.; Gangadin, S.S.; Oomen, P.P.; Judge, G.; Blom, R.E.; Luykx, J.J.; van Beveren, N.J.M.; Veen, N.D.; Kroken, R.A.; Johnsen, E.L. Prednisolone versus placebo addition in the treatment of patients with recent-onset psychotic disorder: A trial design. Trials,  2020, 21(1), 492.
 [http://dx.doi.org/10.1186/s13063-020-04365-4] [PMID: 32513294]

[96]
Jang, S.; Dilger, R.N.; Johnson, R.W. Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J. Nutr.,  2010, 140(10), 1892-1898.
 [http://dx.doi.org/10.3945/jn.110.123273] [PMID: 20685893]

[97]
Dirscherl, K.; Karlstetter, M.; Ebert, S.; Kraus, D.; Hlawatsch, J.; Walczak, Y.; Moehle, C.; Fuchshofer, R.; Langmann, T. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J. Neuroinflammation,  2010, 7(1), 3.
 [http://dx.doi.org/10.1186/1742-2094-7-3] [PMID: 20074346]

[98]
Kim, J.W.; Hong, J.Y.; Bae, S.M. Microglia and autism spectrum disorder: Overview of current evidence and novel immunomodulatory treatment options. Clin. Psychopharmacol. Neurosci.,  2018, 16(3), 246-252.
 [http://dx.doi.org/10.9758/cpn.2018.16.3.246] [PMID: 30121973]

[99]
Wu, Y.; Willcockson, H.H.; Maixner, W.; Light, A.R. Suramin inhibits spinal cord microglia activation and long-term hyperalgesia induced by formalin injection. J. Pain,  2004, 5(1), 48-55.
 [http://dx.doi.org/10.1016/j.jpain.2003.09.006] [PMID: 14975378]

[100]
Cherninskyi, A.; Storozhuk, M.; Maximyuk, O.; Kulyk, V.; Krishtal, O. Triggering of major brain disorders by protons and ATP: The role of ASICs and P2X receptors. Neurosci. Bull.,  2022, 29, 1-18.
 [http://dx.doi.org/10.1007/s12264-022-00986-8] [PMID: 36445556]

[101]
Andoh, M.; Ikegaya, Y.; Koyama, R. Microglia as possible therapeutic targets for autism spectrum disorders. Prog. Mol. Biol. Transl. Sci.,  2019, 167, 223-245.
 [http://dx.doi.org/10.1016/bs.pmbts.2019.06.012] [PMID: 31601405]

[102]
Fan, L.W.; Kaizaki, A.; Tien, L.T.; Pang, Y.; Tanaka, S.; Numazawa, S.; Bhatt, A.J.; Cai, Z. Celecoxib attenuates systemic lipopolysaccharide-induced brain inflammation and white matter injury in the neonatal rats. Neuroscience,  2013, 240, 27-38.
 [http://dx.doi.org/10.1016/j.neuroscience.2013.02.041] [PMID: 23485816]

[103]
Izrael, M.; Slutsky, S.G.; Admoni, T.; Cohen, L.; Granit, A.; Hasson, A.; Itskovitz-Eldor, J.; Krush Paker, L.; Kuperstein, G.; Lavon, N.; Yehezkel Ionescu, S.; Solmesky, L.J.; Zaguri, R.; Zhuravlev, A.; Volman, E.; Chebath, J.; Revel, M. Safety and efficacy of human embryonic stem cell-derived astrocytes following intrathecal transplantation in SOD1G93A and NSG animal models. Stem Cell Res. Ther.,  2018, 9(1), 152.
 [http://dx.doi.org/10.1186/s13287-018-0890-5] [PMID: 29871694]

[104]
Brüstle, O.; Jones, K.N.; Learish, R.D.; Karram, K.; Choudhary, K.; Wiestler, O.D.; Duncan, I.D.; McKay, R.D.G. Embryonic stem cell-derived glial precursors: A source of myelinating transplants. Science,  1999, 285(5428), 754-756.
 [http://dx.doi.org/10.1126/science.285.5428.754] [PMID: 10427001]

[105]
Dimou, L.; Gallo, V. NG 2‐glia and their functions in the central nervous system. Glia,  2015, 63(8), 1429-1451.
 [http://dx.doi.org/10.1002/glia.22859] [PMID: 26010717]

[106]
Sánchez-González, R.; Bribián, A.; López-Mascaraque, L. Cell Fate Potential of NG2 Progenitors. Sci. Rep.,  2020, 10(1), 9876.
 [http://dx.doi.org/10.1038/s41598-020-66753-9] [PMID: 32555386]

[107]
Martín-Moreno, A.M.; Reigada, D.; Ramírez, B.G.; Mechoulam, R.; Innamorato, N.; Cuadrado, A.; de Ceballos, M.L. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: Relevance to Alzheimer’s disease. Mol. Pharmacol.,  2011, 79(6), 964-973.
 [http://dx.doi.org/10.1124/mol.111.071290] [PMID: 21350020]

[108]
Hassan, S.; Eldeeb, K.; Millns, P.J.; Bennett, A.J.; Alexander, S.P.H.; Kendall, D.A. Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation. Br. J. Pharmacol.,  2014, 171(9), 2426-2439.
 [http://dx.doi.org/10.1111/bph.12615] [PMID: 24641282]

[109]
Mattei, D.; Ivanov, A.; Ferrai, C.; Jordan, P.; Guneykaya, D.; Buonfiglioli, A.; Schaafsma, W.; Przanowski, P.; Deuther-Conrad, W.; Brust, P.; Hesse, S.; Patt, M.; Sabri, O.; Ross, T.L.; Eggen, B.J.L.; Boddeke, E.W.G.M.; Kaminska, B.; Beule, D.; Pombo, A.; Kettenmann, H.; Wolf, S.A. Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment. Transl. Psychiatry,  2017, 7(5), e1120.
 [http://dx.doi.org/10.1038/tp.2017.80] [PMID: 28485733]

[110]
Kumar, H.; Sharma, B. Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats. Brain Res.,  2016, 1630, 83-97.
 [http://dx.doi.org/10.1016/j.brainres.2015.10.052] [PMID: 26551768]

[111]
Tsilioni, I.; Taliou, A.; Francis, K.; Theoharides, T.C. Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6. Transl. Psychiatry,  2015, 5(9), e647.
 [http://dx.doi.org/10.1038/tp.2015.142] [PMID: 26418275]

[112]
Theoharides, T.C.; Asadi, S.; Panagiotidou, S. A case series of a luteolin formulation (NeuroProtek®) in children with autism spectrum disorders. Int. J. Immunopathol. Pharmacol.,  2012, 25(2), 317-323.
 [http://dx.doi.org/10.1177/039463201202500201] [PMID: 22697063]

[113]
Parker-Athill, E.; Luo, D.; Bailey, A.; Giunta, B.; Tian, J.; Shytle, R.D.; Murphy, T.; Legradi, G.; Tan, J. Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J. Neuroimmunol.,  2009, 217(1-2), 20-27.
 [http://dx.doi.org/10.1016/j.jneuroim.2009.08.012] [PMID: 19766327]

[114]
Naviaux, J.C.; Schuchbauer, M.A.; Li, K.; Wang, L.; Risbrough, V.B.; Powell, S.B.; Naviaux, R.K. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Transl. Psychiatry,  2014, 4(6), e400.
 [http://dx.doi.org/10.1038/tp.2014.33] [PMID: 24937094]

[115]
Naviaux, R.K.; Curtis, B.; Li, K.; Naviaux, J.C.; Bright, A.T.; Reiner, G.E.; Westerfield, M.; Goh, S.; Alaynick, W.A.; Wang, L.; Capparelli, E.V.; Adams, C.; Sun, J.; Jain, S.; He, F.; Arellano, D.A.; Mash, L.E.; Chukoskie, L.; Lincoln, A.; Townsend, J. Low-dose suramin in autism spectrum disorder: A small, phase I/II, randomized clinical trial. Ann. Clin. Transl. Neurol.,  2017, 4(7), 491-505.
 [http://dx.doi.org/10.1002/acn3.424] [PMID: 28695149]

[116]
Niederhofer, H.; Staffen, W.; Mair, A. Immunoglobulins as an alternative strategy of psychopharmacological treatment of children with autistic disorder. Neuropsychopharmacology,  2003, 28(5), 1014-1015.
 [http://dx.doi.org/10.1038/sj.npp.1300130] [PMID: 12700706]

[117]
Magga, J.; Puli, L.; Pihlaja, R.; Kanninen, K.; Neulamaa, S.; Malm, T.; Härtig, W.; Grosche, J.; Goldsteins, G.; Tanila, H.; Koistinaho, J.; Koistinaho, M. Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer’s disease. J. Neuroinflammation,  2010, 7(1), 90.
 [http://dx.doi.org/10.1186/1742-2094-7-90] [PMID: 21138577]

[118]
Asadabadi, M.; Mohammadi, M.R.; Ghanizadeh, A.; Modabbernia, A.; Ashrafi, M.; Hassanzadeh, E.; Forghani, S.; Akhondzadeh, S. Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: A randomized, double-blind, placebo-controlled trial. Psychopharmacology (Berl.),  2013, 225(1), 51-59.
 [http://dx.doi.org/10.1007/s00213-012-2796-8] [PMID: 22782459]

[119]
Kaizaki, A.; Tien, L.T.; Pang, Y.; Cai, Z.; Tanaka, S.; Numazawa, S.; Bhatt, A.J.; Fan, L.W. Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide. J. Neuroinflammation,  2013, 10(1), 818.
 [http://dx.doi.org/10.1186/1742-2094-10-45] [PMID: 23561827]

[120]
Sun, Y.; Peng, L.; Sun, X.; Bo, J.; Yang, D.; Zheng, Y.; Liu, C.; Zhu, B.; Ma, Z.; Gu, X. Intrathecal injection of spironolactone attenuates radicular pain by inhibition of spinal microglia activation in a rat model. PLoS One,  2012, 7(6), e39897.
 [http://dx.doi.org/10.1371/journal.pone.0039897] [PMID: 22768159]

[121]
Bradstreet, J.J.; Smith, S.; Granpeesheh, D.; El-Dahr, J.M.; Rossignol, D. Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders. Med. Hypotheses,  2007, 68(5), 979-987.
 [http://dx.doi.org/10.1016/j.mehy.2006.10.015] [PMID: 17150311]
Rights & Permissions Print Cite
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1570159X21666221221142743	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190
Current Neuropharmacology

Modelling the Interplay Between Neuron-Glia Cell Dysfunction and Glial Therapy in Autism Spectrum Disorder

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract
