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PERK Regulates Working Memory and Protein Synthesis-Dependent Memory Flexibility.

Siying Zhu1, Keely Henninger1, Barbara C McGrath1

  • 1Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, Pennsylvania, United States of America.

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Protein kinase PERK (EIF2AK3) regulates both protein synthesis-dependent memory flexibility and calcium-dependent working memory. This study reveals a novel role for PERK in cognitive functions.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cognitive Science

Background:

  • PERK (EIF2AK3) is an ER-resident kinase crucial for protein synthesis-dependent processes like memory flexibility.
  • Its role in protein synthesis-independent cognitive functions, such as working memory, remains largely unexplored.

Purpose of the Study:

  • To investigate the function of PERK in working memory, a cognitive process reliant on cellular calcium (Ca2+) dynamics rather than new protein synthesis.
  • To elucidate PERK's novel role in cognitive functions beyond its known involvement in protein synthesis.

Main Methods:

  • Utilized forebrain-specific Perk knockout mice to assess working memory and fear extinction.
  • Employed pharmacological inhibition of PERK in wild-type mice to evaluate its impact on cognitive performance.
  • Examined the role of PERK in Ca2+-dependent working memory and protein synthesis-dependent memory flexibility.

Main Results:

  • Working memory was significantly impaired in mice with forebrain-specific Perk knockout.
  • Pharmacological inhibition of PERK in wild-type mice led to impaired working memory, mirroring deficits seen in knockout models.
  • PERK inhibition mimicked the fear extinction impairments observed in forebrain-specific Perk knockout mice.

Conclusions:

  • PERK plays a novel and critical role in cognitive functions, including working memory.
  • PERK regulates both Ca2+-dependent working memory and protein synthesis-dependent memory flexibility.
  • These findings suggest PERK as a potential therapeutic target for cognitive disorders.