BK channel blocker paxilline attenuates thalidomide-caused synaptic and cognitive dysfunctions in mice

Thalidomide is a widely prescribed immunomodulatory drug (iMiD) for multiple myeloma, but causes reversible memory loss in humans. However, how thalidomide causes cognitive dysfunction at a cellular and molecular level has not been demonstrated. We studied the effect of thalidomide on synaptic funct...

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Published inScientific reports Vol. 8; no. 1; pp. 17653 - 9
Main Authors Choi, Tae-Yong, Lee, Seung-Hyun, Kim, Soo-Jeong, Jo, Youhwa, Park, Chul-Seung, Choi, Se-Young
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 05.12.2018
Nature Publishing Group UK
Subjects
Anxiety
Avoidance behavior
Calcium conductance
Channel gating
Cognitive ability
Excitatory postsynaptic potentials
Immunomodulation
Learning behavior
Memory
Multiple myeloma
Pattern recognition
Potassium
Potassium conductance
Thalidomide
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Summary:Thalidomide is a widely prescribed immunomodulatory drug (iMiD) for multiple myeloma, but causes reversible memory loss in humans. However, how thalidomide causes cognitive dysfunction at a cellular and molecular level has not been demonstrated. We studied the effect of thalidomide on synaptic functions and cognitive behaviors using a mouse model. Thalidomide led to cognitive deficits in learning behavior in a passive avoidance test and in a novel object recognition test, increased anxiety in an elevated plus maze test, and increased depressive behaviors in a tail suspension test. Interestingly, thalidomide elevated big- or large-conductance, calcium-activated K (BK) channel expression in the plasma membrane and BK channel activity in the hippocampus. Thalidomide also increased the paired pulse ratio of excitatory postsynaptic current (EPSC), which suggests a decreased probability of glutamate release. Furthermore, the changes in the paired pulse ratio and in BK channel activity were blocked by paxilline, a BK channel blocker. Finally, we found that thalidomide-induced cognitive dysfunctions were restored by paxilline treatment. These results suggest that thalidomide-mediated BK channel hyperfunction is responsible for the pathological mechanism of thalidomide-associated reversible memory loss.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-36367-3