Neuron-microglia contact-dependent mechanisms attenuate methamphetamine-induced microglia reactivity and enhance neuronal plasticity

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 3; pp. 1 - 17
• Main Authors: Bravo, Joana, Ribeiro, Inês Moreira, Terceiro, Ana Filipa, Andrade, Elva B., Portugal, Camila Cabral, Lopes, Igor M., Azevedo, Maria M., Sousa, Mafalda, Lopes, Cátia D. F., Lobo, Andrea C., Canedo, Teresa, Relvas, João Bettencourt, Summavielle, Teresa
• Format: Journal Article
• Language: English
• Published: Multidisciplinary Digital Publishing Institute (MDPI) 21-01-2022
• Subjects: CD200; Methamphetamine; Neuroprotection; PSD95; Science & Technology
• ISSN: 2073-4409
• DOI: 10.3390/cells11030355

Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP 3 R2-Ca 2+ -dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation.
This work was funded by national funds through FCT—Fundação para a Ciência e a Tecnologia, I.P., under the project UIDB/04293/2020, by FEDER—Fundo Europeu de Desenvolvimento Regional—funds through the COMPETE 2020—Operational Program for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência (FCT), Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-030647 (PTDC/SAU-TOX/30647/2017) in T.S. lab. FEDER Portugal (Norte-01-0145-FEDER-000008000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); FCOMP-01-0124-FEDER-021333). E.B.A. and C.C.P. employment contracts are financed by national funds through FCT in the context of CEEC (CEECIND/03675/2018 to EBA) and the program contract described in paragraphs 4, 5, and 6 of art. 23 of Law no. 57/2016, of August 29, as amended by Law no. 57/2017 of July 2019. J.B., I.R., A.F.T., and T.C. were supported by FCT (PD/BD/135450/2017, 2020.08365.BD, 2020.07188.BD, SFRH/BD/117148/2016). C.D.F.L. was financed in the framework of the project PTDC/EMD-EMD/31540/2017 (POCI-01-0145-FEDER-031540).