Neuron–Microglia Contact-Dependent Mechanisms Attenuate Methamphetamine-Induced Microglia Reactivity and Enhance Neuronal Plasticity

Abstract

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/IP3R2-Ca2+-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.

Role of Microglia in Psychostimulant Addiction

“…It has been shown that METH induces different inflammatory mediators via activation of the NF-κB and other pathways in N9 and BV2 microglial cell lines [ 136 - 138 ]. On the other hand, Canedo et al (2016), Frank et al (2021) and Bravo et al (2022) have showed that METH can not directly activate microglial cells in primary cell culture models [ 37 , 150 , 238 ]. Instead, glutamate and TNF-α released by astrocytes mediated METH-induced microglial activation.…”

Microfluidic Brain‐on‐a‐Chip: From Key Technology to System Integration and Application

“…Bravo et al first verified on a microfluidic device that there is no contact/a noncontact-dependent mechanism for signal communication between hippocampal neurons and microglia exposed to methamphetamine stimulation. [135] Ndyabawe et al developed a BoC with a neural network representing multiple brain regions. Human neural stem cells were placed in different culture cells of perfusion-free microdevices and injected into dopaminergic neurons and GABA neurons, limiting the spread of chemical agents between cell cultures.…”

“…first verified on a microfluidic device that there is no contact/a noncontact‐dependent mechanism for signal communication between hippocampal neurons and microglia exposed to methamphetamine stimulation. [ 135 ] Ndyabawe et al. developed a BoC with a neural network representing multiple brain regions.…”

Meta-analysis of molecular imaging of translocator protein in major depression

“…Microglia are the resident macrophages of the brain, accounting for 5–10% of all cells in the central nervous system ( Pelvig et al, 2008 ; Mondelli et al, 2017 ). In the healthy CNS, microglia are habitually present in a dormant state with ramified morphology, but nonetheless release neurotrophic factors that contribute to the regulation of synaptic homeostasis, especially in the contexts of neurotoxic or traumatic brain injury ( Rodríguez-Gómez et al, 2020 ; Bravo et al, 2022 ). Indeed, a diverse range of factors can provoke microglial activation and changes in morphological phenotype ( Wolf et al, 2017 ), for example in response to a high dietary intake of sucrose ( Patkar et al, 2021 ), which is a characteristic of modern western diets.…”