Activation of PERK elicits memory impairment through inactivation of CREB and downregulation of PSD95 after traumatic brain injury

Tanusree Sen, Rajaneesh Gupta, Helen Kaiser, Nilkantha Sen

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

The PKR-like ER kinase (PERK), a transmembrane protein, resides in the endoplasmic reticulum (ER). Its activation serves as a key sensor of ER stress, which has been implicated in traumatic brain injury (TBI). The loss of memory is one of the most common symptoms after TBI, but the precise role of PERK activation in memory impairment after TBI has not been well elucidated. Here, we have shown that blocking the activation of PERK using GSK2656157 prevents the loss of dendritic spines and rescues memory deficits after TBI. To elucidate the molecular mechanism, we found that activated PERK phosphorylates CAMP response element binding protein (CREB) and PSD95 directly at the S129 and T19 residues, respectively. Phosphorylation of CREB protein prevents its interaction with a coactivator, CREB-binding protein, and subsequently reduces the BDNF level after TBI. Conversely, phosphorylation of PSD95 leads to its downregulation in pericontusional cortex after TBI in male mice. Treatment with either GSK2656157 or overexpression of a kinase-dead mutant of PERK (PERK-K618A) rescues BDNF and PSD95 levels in the pericontusional cortex by reducing phosphorylation of CREB and PSD95 proteins after TBI. Similarly, administration of either GSK2656157 or overexpression of PERK-K618A in primary neurons rescues the loss of dendritic outgrowth and number of synapses after treatment with a PERK activator, tunicamycin. Therefore, our study suggests that inhibition of PERK phosphorylation could be a potential therapeutic target to restore memory deficits after TBI.

Original languageEnglish (US)
Pages (from-to)5900-5911
Number of pages12
JournalJournal of Neuroscience
Volume37
Issue number24
DOIs
StatePublished - Jun 14 2017

Keywords

  • CREB
  • GSK3B
  • PERK
  • PSD95
  • TBI

ASJC Scopus subject areas

  • Neuroscience(all)

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