Abstract
Here, we report a novel target of the drug memantine, ATP-sensitive K + (K ATP ) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in Alzheimer's model APP23 mice. Memantine increased CaMKII activity in the APP23 mouse hippocampus, and memantine-induced enhancement of hippocampal long-term potentiation (LTP) and CaMKII activity was totally abolished by treatment with pinacidil, a specific opener of K ATP channels. Memantine also inhibited Kir6.1 and Kir6.2 K ATP channels and elevated intracellular Ca 2+ concentrations in neuro2A cells overexpressing Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed at postsynaptic regions of hippocampal neurons, whereas Kir6.1 was predominant in dendrites and cell bodies of pyramidal neurons. Finally, we confirmed that Kir6.2 mutant mice exhibit severe memory deficits and impaired hippocampal LTP, impairments that cannot be rescued by memantine administration. Altogether, our studies show that memantine modulates Kir6.2 activity, and that the Kir6.2 channel is a novel target for therapeutics to improve memory impairment in Alzheimer disease patients.
Original language | English (US) |
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Pages (from-to) | 211-221 |
Number of pages | 11 |
Journal | Molecular Psychiatry |
Volume | 23 |
Issue number | 2 |
DOIs | |
State | Published - Feb 1 2018 |
Funding
This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health and Welfare of Japan (22390109 to KF; 20790398 to SM). Also, thanks to Professor Tsuyoshi Miyakawa for providing CaMKIIα +/ − mice and Professor Susumu Seino for providing Kir6.1 +/ − and Kir6.2 − / − mice. We also thank Novartis Pharma for providing APP23 mice. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health and Welfare of Japan (22390109 to KF; 20790398 to SM). Also, thanks to Professor Tsuyoshi Miyakawa for providing CaMKIIα +/-mice and Professor Susumu Seino for providing Kir6.1 +/-and Kir6.2-/-mice. We also thank Novartis Pharma for providing APP23 mice.
ASJC Scopus subject areas
- Molecular Biology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience