Memantine treatment reduces the expression of the K⁺/Cl^- cotransporter KCC2 in the hippocampus and cerebral cortex, and attenuates behavioural responses mediated by GABA_A receptor activation in mice

A 7-day treatment with memantine (25 mg/kg, i.p.), a drug that is currently prescribed for the treatment of Alzheimer's disease, increased the levels of brain-derived neurotrophic factor (BDNF) and reduced the expression of the neuron-specific K⁺/Cl^- co-transporter, KCC2, in the hippocampus and cerebral cortex of mice. Knowing that KCC2 maintains low intracellular Cl^- concentrations, which drive Cl^- influx in response to GABA_A receptor activation, we monitored the behavioural response to the GABA_A receptor enhancer, diazepam, in mice pre-treated for 7 days with saline or 25 mg/kg of memantine. Memantine treatment substantially attenuated motor impairment induced by an acute challenge with diazepam (6 mg/kg, i.p.), as assessed by the rotarod test and the horizontal wire test. We suggest that a prolonged treatment with memantine induces changes in the activity of GABA_A receptors that might contribute to the therapeutic and/or toxic effects of the drug.