Pharmacological Tools to Activate Microglia and their Possible use to Study Neural Network Patho-physiology

Abstract

BackgroundMicroglia are the resident immunocompetent cells of the CNS and also constitute a unique cell type that contributes to neural network homeostasis and function. Understanding microglia cell-signaling not only will reveal their diverse functions but also will help to identify pharmacological and non-pharmacological tools to modulate the activity of these cells.MethodsWe undertook a search of bibliographic databases for peer-reviewed research literature to identify microglial activators and their cell-specificity. We also looked for their effects on neural network function and dysfunction.ResultsWe identified several pharmacological targets to modulate microglial function, which are more or less specific (with the proper control experiments). We also identified pharmacological targets that would require the development of new potent and specific modulators. We identified a wealth of evidence about the participation of microglia in neural network function and their alterations in pathological conditions.ConclusionThe identification of specific microglia-activating signals provides experimental tools to modulate the activity of this heterogeneous cell type in order to evaluate its impact on other components of the nervous system, and it also helps to identify therapeutic approaches to ease some pathological conditions related to microglial dysfunction.

Piezo1 channel‐mediated Ca2+ signaling inhibits lipopolysaccharide‐induced activation of the NF‐κB inflammatory signaling pathway and generation of TNF‐α and IL‐6 in microglial cells

“…It is well established that microglial cells express intrinsic mechanisms for detecting and responding to diverse chemical signals (Pena-Ortega, 2017). For example, they express the CX3CR1 fractalkine receptor that binds chemokine CX3CL1 produced by neurons (Liu et al, 2015) and the C3a receptor responsible for C3a-induced complement signaling in astrocytes (Wei et al, 2021), both interactions being crucial for bidirectional communications between microglial cells and other cell types within the CNS.…”

Fractalkine/CX3CR1-Dependent Modulation of Synaptic and Network Plasticity in Health and Disease

“…For example, the microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity [183]. Besides, microglia almost exclusively express the purinergic receptor P2RY12 [183][184][185][186], whose pharmacological inhibition prevents the neuronal activity-induced synaptic recruitment of microglial protrusions and reduces microglia baseline motility [183], indicating that activity-dependent synaptic ATP release can function as a local chemoattractant that leads to the recruitment of microglia protrusions to active synapses [183]. Once microglial protrusions contact spines, an increase in the frequency of spine calcium transients is observed [177].…”

“…Microglial depletion is a common tool used to understand the role of microglia in neuronal activity [45,184,[188][189][190]. From these experiments, we can summarize that normal microglia activity is required for brain function and plasticity [45,[188][189][190][191].…”

Interactions of neuroimmune signaling and glutamate plasticity in addiction

“…In particular, purinergic P2X7 receptors, which are expressed by astroglia and microglia and activated by extracellular ATP, stand out as key elements of the purinergic system that are linked to physiological underpinnings of drug reward, reinforcement, and relapse. Activation of P2X7 receptors causes microglia to become activated and release endogenous substrates, including glutamate, dopamine, pro-inflammatory cytokines (e.g., IL-1β, IL-6 and TNFα), and reactive oxygen species, that facilitate psychostimulant reward and reinforcement [ 91 , 92 , 127 , 245 ], suggesting a link between the pro-inflammatory actions of P2X7 and CNS diseases. Recent evidence indicates that P2X7 receptor blockade with the competitive, reversible P2X7 antagonist A438079 inhibits facilitation of intracranial self-stimulation (ICSS) by the psychostimulant methylenedioxypyrovalerone (MDPV), a “bath salt” synthetic cathinone with a mechanism of action similar to cocaine but with enhanced potency in blocking dopamine transporters [ 26 , 102 ].…”