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Updated: Oct 23, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine
Teresa Canedo1,2, Camila Cabral Portugal3, Renato Socodato4
1Addiction Biology Group, i3S-Instituto de Investigação e Inovação em Saúde and IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
Abstract:
Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.
Insights
Binge methamphetamine exposure causes neuroinflammation and behavioral deficits by activating microglia. This process involves communication between astrocytes and microglia, which can be blocked to restore normal behavior.
Area of Science:
- Neuroscience
- Neuroinflammation
- Neuropharmacology
Background:
- Methamphetamine (Meth) is a psychostimulant causing neuroinflammation, synaptic dysfunction, and behavioral deficits.
- Aberrant microglial activation is a hallmark of neuroinflammatory disorders.
Purpose of the Study:
- Investigate mechanisms of Meth-induced microglial activation in adult mice.
- Elucidate the role of astrocyte-microglia crosstalk in Meth's neuroinflammatory effects.
Main Methods:
- Examined microgliosis and risk assessment behavior following binge Meth exposure in mice.
- Investigated molecular pathways involving astrocytes, TNF, calcium, and glutamate exocytosis.
- Utilized genetic ablation of TNF and pharmacological suppression of astrocytic calcium.
Main Results:
- Binge Meth exposure induced microgliosis and disrupted risk assessment behavior.
- These effects were dependent on astrocyte-to-microglia crosstalk, specifically TNF production and calcium mobilization from astrocytes.
- Blocking TNF or astrocytic calcium prevented Meth-induced microglial reactivity and restored normal behavior.
Conclusions:
- Glial crosstalk, particularly between astrocytes and microglia, is crucial for mediating Meth-induced neuroinflammation and behavioral changes.
- Targeting astrocytic TNF production or calcium signaling may offer therapeutic strategies for Meth abuse consequences.
