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. 2020 Oct;155(1):45-61.
doi: 10.1111/jnc.15018. Epub 2020 May 10.

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

Zakhar O Shenkarev  1   2 , Mikhail A Shulepko  1 , Maxim L Bychkov  1 , Dmitrii S Kulbatskii  1 , Olga V Shlepova  1   2 , Nathalia A Vasilyeva  3   4 , Alexander A Andreev-Andrievskiy  3   5 , Anfisa S Popova  3   5 , Evgeniya A Lagereva  5 , Eugene V Loktyushov  3 , Sergey G Koshelev  1 , Morten S Thomsen  6 , Dmitry A Dolgikh  1 , Sergey A Kozlov  1 , Pavel M Balaban  3   4 , Mikhail P Kirpichnikov  1   3 , Ekaterina N Lyukmanova  1   2
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Free article

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

Zakhar O Shenkarev et al. J Neurochem. 2020 Oct.
Free article

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 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.

Keywords: Ly6/uPAR; cognitive function; long-term potentiation; neurodegeneration; nicotinic acetylcholine receptor; positive allosteric modulator.

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References

REFERENCES

    1. Andriambeloson, E., Huyard, B., Poiraud, E., & Wagner, S. (2014). Methyllycaconitine- and scopolamine-induced cognitive dysfunction: Differential reversal effect by cognition-enhancing drugs. Pharmacol Res Perspect, 2, e00048. https://doi.org/10.1002/prp2.48
    1. Barco, A., Alarcon, J. M., & Kandel, E. R. (2002). Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell, 108, 689-703. https://doi.org/10.1016/S0092-8674(02)00657-8
    1. Biton, B., Bergis, O. E., Galli, F., Nedelec, A., Lochead, A. W., Jegham, S., … Scatton, B. (2007). SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile. Neuropsychopharmacology, 32, 1-16.
    1. Bychkov, M. L., Vasilyeva, N. A., Shulepko, M. A., Balaban, P. M., Kirpichnikov, M. P., & Lyukmanova, E. N. (2018). Lynx1 prevents long-term potentiation blockade and reduction of neuromodulator expression caused by Aβ1-42 and JNK activation. Acta Naturae, 3, 57-61. https://doi.org/10.32607/20758251-2018-10-3-57-61
    1. Cachelin, A. B., & Rust, G. (1994). Unusual pharmacology of (+)-tubocurarine with rat neuronal nicotinic acetylcholine receptors containing beta 4 subunits. Molecular Pharmacology, 46, 1168-1174.

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