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A calpain-2 selective inhibitor enhances learning & memory by prolonging ERK activation
Yan Liu1, Yubin Wang1, Guoqi Zhu1
1Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Neuropharmacology
|February 25, 2016
Summary
Calpain-2 activation limits learning and memory. Inhibiting calpain-2 with C2I enhances memory in mice, possibly by prolonging ERK activation and affecting SCOP levels.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Calpain-1 is essential for long-term potentiation (LTP) induction.
- Calpain-2 activation restricts LTP magnitude during memory consolidation.
- Selective calpain-2 inhibitors can enhance LTP.
Purpose of the Study:
- To investigate if a calpain-2 inhibitor (C2I) enhances learning and memory in wild-type and calpain-1 knock-out mice.
- To explore the molecular mechanisms underlying C2I's effects on memory.
Main Methods:
- Used a selective calpain-2 inhibitor (C2I) in wild-type and calpain-1 knock-out mice.
- Assessed LTP in hippocampal slices.
- Evaluated fear conditioning and novel object recognition memory tasks.
- Measured protein levels (PTEN, SCOP) and ERK activation.
Main Results:
- C2I reestablished theta burst stimulation-LTP in calpain-1 knock-out mice, an effect blocked by an ERK inhibitor.
- C2I inhibited PTEN degradation in both genotypes.
- Low doses of C2I enhanced fear conditioning and normalized novel object recognition memory in calpain-1 knock-out mice.
- C2I treatment prevented SCOP recovery and prolonged ERK activation.
Conclusions:
- Calpain-2 activation limits learning extent, potentially by restricting ERK activation duration.
- Calpain-2-mediated PTEN degradation influences SCOP synthesis, impacting memory consolidation.
- Targeting calpain-2 offers a potential strategy for cognitive enhancement.
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