Degeneration of basal forebrain (BF) cholinergic neurons is one of the early pathological events in Alzheimer's disease (AD) and is thought to be responsible for the cholinergic and cognitive deficits in AD. The functions of this group of neurons are highly influenced by glutamatergic inputs from neocortex. We found that activation of metabotropic glutamate receptor 7 (mGluR7) decreased NMDAR-mediated currents and NR1 surface expression in rodent BF neurons via a mechanism involving cofilin-regulated actin dynamics. In BF cholinergic neurons, β-amyloid (Aβ) selectively impaired mGluR7 regulation of NMDARs by increasing p21-activated kinase activity and decreasing cofilin-mediated actin depolymerization through a p75NTR-dependent mechanism. Cell viability assays showed that activation of mGluR7 protected BF neurons from NMDA-induced excitotoxicity, which was selectively impaired by Aβ in BF cholinergic neurons. It provides a potential basis for the Aβ-induced disruption of calcium homeostasis that might contribute to the selective degeneration of BF cholinergic neurons in the early stage of AD.
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