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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Current Frontiers

The Role of Microglia in Neurodevelopmental Disorders and their Therapeutics

Author(s): Rachel Coomey, Rianne Stowell, Ania Majewska and Daniela Tropea*

Volume 20, Issue 4, 2020

Page: [272 - 276] Pages: 5

DOI: 10.2174/1568026620666200221172619

Abstract

The development of new therapeutics is critically dependent on an understanding of the molecular pathways, the disruption of which results in neurological symptoms. Genetic and biomarker studies have highlighted immune signalling as a pathway that is impaired in patients with neurodevelopmental disorders (NDDs), and several studies on animal models of aberrant neurodevelopment have implicated microglia, the brain’s immune cells, in the pathology of these diseases. Despite the increasing awareness of the role of immune responses and inflammation in the pathophysiology of NDDs, the testing of new drugs rarely considers their effects in microglia. In this brief review, we present evidence of how the study of microglia can be critical for understanding the mechanisms of action of candidate drugs for NDDs and for increasing their therapeutic effect.

Keywords: Microglia, Neurodevelopmental disorders, Therapeutics, Genetic, Pathophysiology, Immune cells.

[1]
Paolicelli, R.C.; Bolasco, G.; Pagani, F.; Maggi, L.; Scianni, M.; Panzanelli, P.; Giustetto, M.; Ferreira, T.A.; Guiducci, E.; Dumas, L.; Ragozzino, D.; Gross, C.T. Synaptic pruning by microglia is necessary for normal brain development. Science, 2011, 333(6048), 1456-1458.
[http://dx.doi.org/10.1126/science.1202529] [PMID: 21778362]
[2]
Tremblay, M.È.; Lowery, R.L.; Majewska, A.K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol., 2010, 8(11) e1000527
[http://dx.doi.org/10.1371/journal.pbio.1000527] [PMID: 21072242]
[3]
Sipe, G.O.; Lowery, R.L.; Tremblay, M.È.; Kelly, E.A.; Lamantia, C.E.; Majewska, A.K. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat. Commun., 2016, 7(1), 10905.
[http://dx.doi.org/10.1038/ncomms10905] [PMID: 26948129]
[4]
Schafer, D.P.; Lehrman, E.K.; Kautzman, A.G.; Koyama, R.; Mardinly, A.R.; Yamasaki, R.; Ransohoff, R.M.; Greenberg, M.E.; Barres, B.A.; Stevens, B. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron, 2012, 74(4), 691-705.
[http://dx.doi.org/10.1016/j.neuron.2012.03.026] [PMID: 22632727]
[5]
Gunner, G.; Cheadle, L.; Johnson, K.M.; Ayata, P.; Badimon, A.; Mondo, E.; Nagy, M.A.; Liu, L.; Bemiller, S.M.; Kim, K.W.; Lira, S.A.; Lamb, B.T.; Tapper, A.R.; Ransohoff, R.M.; Greenberg, M.E.; Schaefer, A.; Schafer, D.P. Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. Nat. Neurosci., 2019, 22(7), 1075-1088.
[http://dx.doi.org/10.1038/s41593-019-0419-y] [PMID: 31209379]
[6]
Nakayama, H.; Abe, M.; Morimoto, C.; Iida, T.; Okabe, S.; Sakimura, K.; Hashimoto, K. microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron, 2018, 74(4), 691-705.
[7]
Pfeiffer, T.; Avignone, E.; Nägerl, U.V. Induction of hippocampal long-term potentiation increases the morphological dynamics of microglial processes and prolongs their contacts with dendritic spines. Sci. Rep., 2016, 6(1), 32422.
[http://dx.doi.org/10.1038/srep32422] [PMID: 27604518]
[8]
Jung, S.; Aliberti, J.; Graemmel, P.; Sunshine, M.J.; Kreutzberg, G.W.; Sher, A.; Littman, D.R. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol., 2000, 20(11), 4106-4114.
[http://dx.doi.org/10.1128/MCB.20.11.4106-4114.2000] [PMID: 10805752]
[9]
Xu, N.; Li, X.; Zhong, Y. Inflammatory cytokines: potential biomarkers of immunologic dysfunction in autism spectrum disorders. Mediators Inflamm., 2015, 2015 531518
[http://dx.doi.org/10.1155/2015/531518] [PMID: 25729218]
[10]
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]
[11]
Suzuki, K.; Sugihara, G.; Ouchi, Y.; Nakamura, K.; Futatsubashi, M.; Takebayashi, K.; Yoshihara, Y.; Omata, K.; Matsumoto, K.; Tsuchiya, K.J.; Iwata, Y.; Tsujii, M.; Sugiyama, T.; Mori, N. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry, 2013, 70(1), 49-58.
[http://dx.doi.org/10.1001/jamapsychiatry.2013.272] [PMID: 23404112]
[12]
Morgan, J.T.; Chana, G.; Pardo, C.A.; Achim, C.; Semendeferi, K.; Buckwalter, J.; Courchesne, E.; Everall, I.P. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol. Psychiatry, 2010, 68(4), 368-376.
[http://dx.doi.org/10.1016/j.biopsych.2010.05.024] [PMID: 20674603]
[13]
Lee, A.S.; Azmitia, E.C.; Whitaker-Azmitia, P.M. Developmental microglial priming in postmortem autism spectrum disorder temporal cortex. Brain Behav. Immun., 2017, 62, 193-202.
[http://dx.doi.org/10.1016/j.bbi.2017.01.019] [PMID: 28159644]
[14]
Velmeshev, D.; Schirmer, L.; Jung, D.; Haeussler, M.; Perez, Y.; Mayer, S.; Bhaduri, A.; Goyal, N.; Rowitch, D.H.; Kriegstein, A.R. Single-cell genomics identifies cell type-specific molecular changes in autism. Science, 2019, 364(6441), 685-689.
[http://dx.doi.org/10.1126/science.aav8130] [PMID: 31097668]
[15]
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., 2019, 1-9. Epub ahead of print
[http://dx.doi.org/10.1017/S1092852919001603] [PMID: 31659946]
[16]
Wang, Y.; Zhao, S.; Liu, X.; Zheng, Y.; Li, L.; Meng, S. Oxytocin improves animal behaviors and ameliorates oxidative stress and inflammation in autistic mice. Biomed. Pharmacother., 2018, 107, 262-269.
[http://dx.doi.org/10.1016/j.biopha.2018.07.148] [PMID: 30098544]
[17]
Amir, R.E.; Van den Veyver, I.B.; Wan, M.; Tran, C.Q.; Francke, U.; Zoghbi, H.Y. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet., 1999, 23(2), 185-188.
[http://dx.doi.org/10.1038/13810] [PMID: 10508514]
[18]
Nagarajan, R.P.; Hogart, A.R.; Gwye, Y.; Martin, M.R.; LaSalle, J.M. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics, 2006, 1(4), e1-e11.
[http://dx.doi.org/10.4161/epi.1.4.3514] [PMID: 17486179]
[19]
Maezawa, I.; Jin, L.W. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J. Neurosci., 2010, 30(15), 5346-5356.
[http://dx.doi.org/10.1523/JNEUROSCI.5966-09.2010] [PMID: 20392956]
[20]
Derecki, N.C.; Cronk, J.C.; Lu, Z.; Xu, E.; Abbott, S.B.; Guyenet, P.G.; Kipnis, J. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature, 2012, 484(7392), 105-109.
[http://dx.doi.org/10.1038/nature10907] [PMID: 22425995]
[21]
Wang, J.; Wegener, J.E.; Huang, T.W.; Sripathy, S.; De Jesus-Cortes, H.; Xu, P.; Tran, S.; Knobbe, W.; Leko, V.; Britt, J.; Starwalt, R.; McDaniel, L.; Ward, C.S.; Parra, D.; Newcomb, B.; Lao, U.; Nourigat, C.; Flowers, D.A.; Cullen, S.; Jorstad, N.L.; Yang, Y.; Glaskova, L.; Vingeau, S.; Kozlitina, J.; Yetman, M.J.; Jankowsky, J.L.; Reichardt, S.D.; Reichardt, H.M.; Gärtner, J.; Bartolomei, M.S.; Fang, M.; Loeb, K.; Keene, C.D.; Bernstein, I.; Goodell, M.; Brat, D.J.; Huppke, P.; Neul, J.L.; Bedalov, A.; Pieper, A.A. Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature, 2015, 521(7552), E1-E4.
[http://dx.doi.org/10.1038/nature14444] [PMID: 25993969]
[22]
Zhao, D.; Mokhtari, R.; Pedrosa, E.; Birnbaum, R.; Zheng, D.; Lachman, H.M. Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress. Mol. Autism, 2017, 8(1), 17.
[http://dx.doi.org/10.1186/s13229-017-0134-z] [PMID: 28367307]
[23]
Cronk, J.C.; Derecki, N.C.; Ji, E.; Xu, Y.; Lampano, A.E.; Smirnov, I.; Baker, W.; Norris, G.T.; Marin, I.; Coddington, N.; Wolf, Y.; Turner, S.D.; Aderem, A.; Klibanov, A.L.; Harris, T.H.; Jung, S.; Litvak, V.; Kipnis, J. Methyl-CpG binding protein 2 regulates microglia and macrophage gene expression in response to inflammatory stimuli. Immunity, 2015, 42(4), 679-691.
[http://dx.doi.org/10.1016/j.immuni.2015.03.013] [PMID: 25902482]
[24]
Schafer, D.P.; Heller, C.T.; Gunner, G.; Heller, M.; Gordon, C.; Hammond, T.; Wolf, Y.; Jung, S.; Stevens, B. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. eLife, 2016, 5 e15224
[http://dx.doi.org/10.7554/eLife.15224] [PMID: 27458802]
[25]
Horiuchi, M.; Smith, L.; Maezawa, I.; Jin, L.W. CX3CR1 ablation ameliorates motor and respiratory dysfunctions and improves survival of a Rett syndrome mouse model. Brain Behav. Immun., 2017, 60, 106-116.
[http://dx.doi.org/10.1016/j.bbi.2016.02.014] [PMID: 26883520]
[26]
Nance, E.; Kambhampati, S.P.; Smith, E.S.; Zhang, Z.; Zhang, F.; Singh, S.; Johnston, M.V.; Kannan, R.M.; Blue, M.E.; Kannan, S. Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome. J. Neuroinflammation, 2017, 14(1), 252.
[http://dx.doi.org/10.1186/s12974-017-1004-5] [PMID: 29258545]
[27]
Deepmala, S.J.; Slattery, J.; Kumar, N.; Delhey, L.; Berk, M.; Dean, O.; Spielholz, C.; Frye, R. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci. Biobehav. Rev., 2015, 55, 294-321.
[http://dx.doi.org/10.1016/j.neubiorev.2015.04.015] [PMID: 25957927 ]
[28]
Hardan, A.Y.; Fung, L.K.; Libove, R.A.; Obukhanych, T.V.; Nair, S.; Herzenberg, L.A.; Frazier, T.W.; Tirouvanziam, R. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol. Psychiatry, 2012, 71(11), 956-961.
[http://dx.doi.org/10.1016/j.biopsych.2012.01.014] [PMID: 22342106]
[29]
Erny, D.; Hrabě de Angelis, A.L.; Jaitin, D.; Wieghofer, P.; Staszewski, O.; David, E.; Keren-Shaul, H.; Mahlakoiv, T.; Jakobshagen, K.; Buch, T.; Schwierzeck, V.; Utermöhlen, O.; Chun, E.; Garrett, W.S.; McCoy, K.D.; Diefenbach, A.; Staeheli, P.; Stecher, B.; Amit, I.; Prinz, M. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci., 2015, 18(7), 965-977.
[http://dx.doi.org/10.1038/nn.4030] [PMID: 26030851]
[30]
Lebovitz, Y.; Ringel-Scaia, V.M.; Allen, I.C.; Theus, M.H. Emerging developments in microbiome and microglia research: implications for neurodevelopmental disorders. Front. Immunol., 2018, 9, 1993.
[http://dx.doi.org/10.3389/fimmu.2018.01993] [PMID: 30233586]

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