MPTP‐induced changes in hippocampal synaptic plasticity and memory are prevented by memantine through the BDNF‐TrkB pathway

Abstract

BACKGROUND AND PURPOSEMild cognitive deficit in early Parkinson's disease (PD) has been widely studied. Here we have examined the effects of memantine in preventing memory deficit in experimental PD models and elucidated some of the underlying mechanisms. EXPERIMENTAL APPROACHESI.p. injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP) in C57BL/6 mice was used to produce models of PD. We used behavioural tasks to test memory. In vitro, we used slices of hippocampus, with electrophysiological, Western blotting, real time PCR, ELISA and immunochemical techniques. KEY RESULTSFollowing MPTP injection, long-term memory was impaired and these changes were prevented by pre-treatment with memantine. In hippocampal slices from MPTP treated mice, long-term potentiation (LTP) -induced by θ burst stimulation (10 bursts, 4 pulses) was decreased, while long-term depression (LTD) induced by low-frequency stimulation (1 Hz, 900 pulses) was enhanced, compared with control values. A single dose of memantine (i.p., 10 mg·kg −1 ) reversed the decreased LTP and the increased LTD in this PD model. Activity-dependent changes in tyrosine kinase receptor B (TrkB), ERK and brain-derived neurotrophic factor (BDNF) expression were decreased in slices from mice after MPTP treatment. These effects were reversed by pretreatment with memantine. Incubation of slices in vitro with 1-methyl-4-phenylpyridinium (MPP + ) decreased depolarization-induced expression of BDNF. This effect was prevented by pretreatment of slices with memantine or with calpain inhibitor III, suggesting the involvement of an overactivated calcium signalling pathway. CONCLUSIONS AND IMPLICATIONSMemantine should be useful in preventing loss of memory and hippocampal synaptic plasticity in PD models. AbbreviationsDHPG, 3,5-dihydroxyphenylglycine; MPP + ,1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-

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