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Pathological polarizations from microglia to astrocyte contributes to spatial memory deficit in methamphetamine
Yuning Mai1, Zhen Cheng1, Ze Wang1
1Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China.
Abstract:
Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.
Insights
Methamphetamine abstinence impairs spatial memory by promoting M1-like microglia and A1-like astrocytes. Suppressing microglia activation with minocycline during methamphetamine exposure rescues spatial memory deficits.
Area of Science:
- Neuroscience
- Neuroimmunology
- Pharmacology
Background:
- Astrocytes in the dorsal CA1 (dCA1) region of the brain play a crucial role in spatial memory.
- Methamphetamine abstinence is associated with astrocyte polarization and spatial memory deficits.
- The precise mechanisms linking astrocyte polarization to memory impairment and potential therapeutic targets remain largely unknown.
Purpose of the Study:
- To elucidate the underlying mechanisms of astrocyte polarization in methamphetamine-induced spatial memory deficits.
- To investigate the role of microglia-astrocyte interactions in the dCA1 region.
- To evaluate minocycline as a potential therapeutic agent for methamphetamine abstinence-related cognitive impairment.
Main Methods:
- Comparative analysis of M1-like microglia and A1-like astrocytes in the dCA1 of methamphetamine-abstinence mice.
- In vitro studies using BV2 microglia cell medium to assess astrocyte polarization and glutamate uptake.
- Administration of minocycline to suppress M1-like microglia activation in vivo.
- Assessment of spatial memory, dCA1 neurotoxicity, and astrocyte polarization following minocycline treatment.
Main Results:
- Methamphetamine abstinence significantly increased M1-like microglia and A1-like astrocytes in the dCA1, alongside elevated Interleukin-1α and Tumor Necrosis Factor-α.
- M1-like microglia conditioned medium induced A1-like astrocyte polarization and impaired glutamate clearance in vitro.
- Minocycline treatment effectively suppressed M1-like microglia activation, reduced A1-like astrocyte polarization, and ameliorated dCA1 neurotoxicity.
- Minocycline administration during the methamphetamine exposure period, but not during abstinence, rescued spatial memory deficits.
Conclusions:
- M1-like microglia activation and subsequent A1-like astrocyte polarization in the dCA1 are key contributors to spatial memory impairment during methamphetamine abstinence.
- Targeting M1-like microglia with minocycline during the drug exposure phase offers a promising therapeutic strategy to prevent or reverse cognitive deficits associated with methamphetamine abstinence.
