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

  • Sci Rep. 2018 Dec 5;8(1):17653. doi: 10.1038/s41598-018-36367-3.
Tae-Yong Choi  1  2 ,  Seung-Hyun Lee  1 ,  Soo-Jeong Kim  1 ,  Youhwa Jo  1 ,  Chul-Seung Park  3 ,  Se-Young Choi  4
Affiliations
  • 1. Department of Physiology and Dental Research Institute, Seoul National University School of Dentistry, Seoul, 03080, Republic of Korea.
  • 2. Department of Neural Development and Disease, Korea Brain Research Institute, Daegu, 41068, Republic of Korea.
  • 3. School of Life Sciences, Gwangju Institute Science and Technology, Gwangju, 61005, Republic of Korea.
  • 4. Department of Physiology and Dental Research Institute, Seoul National University School of Dentistry, Seoul, 03080, Republic of Korea. [email protected].
PMID: 30518785 DOI: 10.1038/s41598-018-36367-3
Abstract

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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