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

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 pos...

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Published in:Journal of neurochemistry 2020-10, Vol.155 (1), p.45-61
Main Authors: Shenkarev, Zakhar O., Shulepko, Mikhail A., Bychkov, Maxim L., Kulbatskii, Dmitrii S., Shlepova, Olga V., Vasilyeva, Nathalia A., Andreev-Andrievskiy, Alexander A., Popova, Anfisa S., Lagereva, Evgeniya A., Loktyushov, Eugene V., Koshelev, Sergey G., Thomsen, Morten S., Dolgikh, Dmitry A., Kozlov, Sergey A., Balaban, Pavel M., Kirpichnikov, Mikhail P., Lyukmanova, Ekaterina N.
Format: Article
Language:English
Subjects:
Acetylcholine - pharmacology
Acetylcholine receptors (nicotinic)
Adaptor Proteins, Signal Transducing - pharmacokinetics
Adaptor Proteins, Signal Transducing - pharmacology
Alkaloids - pharmacology
Allosteric properties
alpha7 Nicotinic Acetylcholine Receptor - antagonists & inhibitors
Animals
Blood-brain barrier
Blood-Brain Barrier - drug effects
Brain
Brain - metabolism
Brain slice preparation
Cerebellum
Cholinergic transmission
Cholinergics
Cholinesterase Inhibitors - toxicity
Cognitive ability
Cognitive Dysfunction - chemically induced
Cognitive Dysfunction - prevention & control
Cognitive Dysfunction - psychology
cognitive function
Gametocytes
Hippocampus
Impairment
Interneurons
Interneurons - drug effects
Intranasal administration
Learning
Learning - drug effects
Long-Term Potentiation - drug effects
long‐term potentiation
Ly6/uPAR
Male
Memory
Methyllycaconitine
Mice
Mice, Inbred C57BL
Motor skill learning
neurodegeneration
Neuronal Plasticity - drug effects
nicotinic acetylcholine receptor
Olfactory discrimination learning
Oocytes
Plasticity
positive allosteric modulator
Potentiation
Rats
Rats, Wistar
Smell - drug effects
Synaptic plasticity
Visual cortex
Visual Cortex - drug effects
Xenopus laevis
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Summary: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 Xenopus laevis oocytes with IC50 ~ 50 µM. In 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 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. Long‐term potentiation 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. Lynx1 is a GPI‐tethered regulatory protein colocalized with nicotinic acetylcholine receptors (nAChRs) in the brain. We studied the water‐soluble Lynx1 variant lacking GPI‐anchor (ws‐Lynx1). At 2 µM, ws‐Lynx1 potentiates α7‐nAChRs in the rat primary visual cortex L1 interneurons. At higher concentrations, ws‐Lynx1 inhibited α7‐nAChRs. 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, motor learning, and long‐term potentiation impairment induced by methyllycaconitine (MLA). Ws‐Lynx1 en
ISSN:0022-3042
1471-4159
DOI:10.1111/jnc.15018