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Calcium-/Calmodulin-Dependent Protein Kinase II (CaMKII) Inhibition Induces Learning and Memory Impairment and

Jialu Wang1,2, Xiaoxue Xu2, Wanying Jia3

  • 1Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China.

Oxidative Medicine and Cellular Longevity
|January 3, 2022
PubMed
Abstract

Insights

Calcium-/calmodulin- (CaM-) dependent kinase II (CaMKII) inhibition impairs learning, memory, and causes neuronal death, potentially through dysregulated c-Jun N-terminal kinase (JNK) signaling.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Epilepsy Research

Background:

  • Calcium-/calmodulin- (CaM-) dependent kinase II (CaMKII) plays a role in neurological functions.
  • CaMKII inhibition is linked to epilepsy, but mechanisms of cognitive impairment and neuronal death are unclear.

Purpose of the Study:

  • To investigate the role of CaMKII in epileptogenesis using a CaMKII inhibitor.
  • To elucidate the molecular mechanisms underlying learning and memory deficits and neuronal death induced by CaMKII inhibition.

Main Methods:

  • RNA-sequencing to identify differentially expressed genes in hippocampal neurons treated with KN93 (CaMKII inhibitor).
  • Morris water maze test to assess learning and memory impairment.
  • Western blotting, immunohistochemistry, and TUNEL staining to evaluate neuronal death, apoptosis, and signaling pathways.

Main Results:

  • CaMKII inhibition by KN93 reduced cAMP response element-binding (CREB) protein activity, impairing learning and memory in Wistar and tremor rats.
  • CaMKII inhibition led to neuronal death, reactive astrocyte activation, and deregulated mitogen-activated protein kinases in rat hippocampi.
  • Neuronal death and apoptosis were observed in cell cultures treated with KN93, and this effect was reversed by a c-Jun N-terminal kinase (JNK) inhibitor (SP600125).

Conclusions:

  • CaMKII inhibition induces learning and memory impairment and apoptosis.
  • Dysregulated JNK signaling may be a key mechanism contributing to the observed neuronal damage and cognitive deficits.

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