Electro-acupuncture Alleviates METH Withdrawal-induced Spatial Memory Deficits by Restoring Astrocyte-drived Glutamate Uptake in dCA1

Methamphetamine (METH) is frequently abused drug and produces cognitive deficits. METH could induce hyper-glutamatergic state in the brain, which could partially explain METH-related cognitive deficits, but the synaptic etiology remains incompletely understood. To address this issue, we explored the role of dCA1 tripartite synapses and the potential therapeutic effects of electro-acupuncture (EA) in the development of METH withdrawal-induced spatial memory deficits in mice. We found that METH withdrawal weakened astrocytic capacity of glutamate (Glu) uptake, but failed to change Glu release from dCA3, which lead to hyper-glutamatergic excitotoxicity at dCA1 tripartite synapses. By restoring the astrocytic capacity of Glu uptake, EA treatments suppressed the hyper-glutamatergic state and normalized the excitability of postsynaptic neuron in dCA1, finally alleviated spatial memory deficits in METH withdrawal mice. These findings indicate that astrocyte at tripartite synapses might be a key target for developing therapeutic interventions against METH-associated cognitive disorders, and EA represent a promising non-invasive therapeutic strategy for the management of drugs-caused neurotoxicity.