Journal
GLIA
Volume 69, Issue 10, Pages 2404-2418Publisher
WILEY
DOI: 10.1002/glia.24046
Keywords
astrocytes; glutamate clearance; methamphetamine; spatial memory; STAT3
Categories
Funding
- National Natural Science Foundation of China [81571303, 81901353, 82071495]
- Natural Science Foundation of Jiangsu Province [BK20190805, BK20201398]
- Priority Academic Program Development of Jiangsu Higher Education Institutions, Integration of Chinese and Western Medicine
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The study revealed that METH withdrawal disrupted spatial memory in mice, associated with increased Glu levels and postsynaptic neuronal activities at dCA1 synapses. METH withdrawal weakened the capacity of Glu clearance in astrocytes, while it did not affect the presynaptic Glu release from dCA3 within dCA1.
Methamphetamine (METH) is a common abused drug. METH-triggered glutamate (Glu) levels in dorsal CA1 (dCA1) could partially explain the etiology of METH-caused abnormal memory, but the synaptic mechanism remains unclear. Here, we found that METH withdrawal disrupted spatial memory in mice, accompanied by the increases in Glu levels and postsynaptic neuronal activities at dCA1 synapses. METH withdrawal weakened the capacity of Glu clearance in astrocytes, as indicated by increasing the A1-like astrocytes and phosphorylated signal transducer and activator of transcription 3 (p-STAT3), decreasing the Glu transporter 1(GLT-1, also known as EAAT2 or SLC1A2), Glu-aspartate-transporter (GLAST also known as EAAT1 or SLC1A3) and astrocytic glutamine synthase (GS), but failed to affect the presynaptic Glu release from dCA3 within dCA1. Moreover, we identified that in vitro A1-like astrocytes exhibited an increased STAT3 activation and the impaired capacity of Glu clearance. Most importantly, selective knockdown of astrocytic STAT3 in vivo in dCA1 restored the astrocytic capacity of Glu clearance, normalized Glu levels at dCA1 synapses, and finally rescued METH withdrawal-disrupted spatial memory in mice. Thus, astrocytic Glu clearance system, especially STAT3, serves as a novel target for future therapies against METH neurotoxicity.
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