Water‐soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with α7‐nAChR dysfunction

Abstract

Lynx1 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 positive 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 concentrations ws‐Lynx1 inhibits α7‐nAChRs expressed in X. 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 methyllycaconitine (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‐administration. 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 nAChR subunit and their association in the mouse brain . Our findings suggest that endogenous Lynx1 limits α7‐nAChRs activation in the adult brain. Ws‐Lynx1 partially displaces Lynx1 causing positive modulation of α7‐nAChRs and enhancement of synaptic plasticity. Ws‐Lynx1 and similar compounds may constitute useful hits for treatment of cognitive deficits associated with the cholinergic system dysfunction.