Water ‐Soluble Variant of Human Lynx1 Positively Modulates Synaptic Plasticity and Ameliorates Cognitive Impairment Associated with a7‐nAChR Dysfunction

AbstractLynx1 is a GPI ‐tethered protein colocalized with nicotinic acetylcholine receptors (nAChRs) in the brain areas important for learning and memory. Previously we demonstrated that at low micromolar concentrations the water‐soluble Lynx1 variant lacking GPI‐anchor (ws‐Lynx1) acts on α7‐nAChRs as a positiv e allosteric modulator. We hypothesized that ws‐Lynx1 could be used for improvement of cognitive processes dependent on nAChRs. Here we showed that 2 µM ws‐Lynx1 increased the acetylcholine‐evoked current at α7‐nAChRs in the rat primary visual cortex L1 interneurons. At higher concentratio ns ws‐Lynx1 inhibits α7‐nAChRs expressed inX. laevis oocytes with IC50 ~50 µM. In C57BL/6 mice, ws‐Lynx1 penetrated the blood‐brain barrier upon intranasal administration and accumulated in the cortex, hippocampus, and cerebellum. Chronic ws‐Lynx1 treatment prevented the olfactory memory and motor learning impairment induced by the α7‐nAChRs inhibitor methyllycac onitine (MLA). Enhanced long‐term potentiation (LTP) and increased paired‐pulse facilitation ratio were observed in the hippocampal slices incubated with ws‐Lynx1 and in the slices from ws‐Lynx1‐treated mice. LTP blockade observed in MLA‐treated mice was abolished by ws‐Lynx1 co‐admi nistration. To understand the mechanism of ws‐Lynx1 action, we studied the interaction of ws‐Lynx1 and MLA at α7‐nAChRs, measured the basal concentrations of endogenous Lynx1 and the α7...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research