Altered regulation of protein kinase a activity in the medial prefrontal cortex of normal and brain-injured animals actively engaged in a working memory task

J Neurotrauma. 2015 Jan 15;32(2):139-48. doi: 10.1089/neu.2014.3487. Epub 2014 Nov 13.


Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling is required for short- and long-term memory. In contrast, enhanced PKA activity has been shown to impair working memory, a prefrontal cortex (PFC)-dependent, transient form of memory critical for cognition and goal-directed behaviors. Working memory can be impaired after traumatic brain injury (TBI) in the absence of overt damage to the PFC. The cellular and molecular mechanisms that contribute to this deficit are largely unknown. In the present study, we examined whether altered PKA signaling in the PFC as a result of TBI is a contributing mechanism. We measured PKA activity in medial PFC (mPFC) tissue homogenates prepared from sham and 14-day postinjury rats. PKA activity was measured both when animals were inactive and when actively engaged in a spatial working memory task. Our results demonstrate, for the first time, that PKA activity in the mPFC is actively suppressed in uninjured animals performing a working memory task. By comparison, both basal and working memory-related PKA activity was elevated in TBI animals. Inhibition of PKA activity by intra-mPFC administration of Rp-cAMPS into TBI animals had no influence on working memory performance 30 min postinfusion, but significantly improved working memory when tested 24 h later. This improvement was associated with reduced glutamic acid decarboxylase 67 messenger RNA levels. Taken together, these results suggest that TBI-associated working memory dysfunction may result, in part, from enhanced PKA activity, possibly leading to altered expression of plasticity-related genes in the mPFC.

Keywords: CREB; PKA signaling; memory; prefrontal cortex; traumatic brain injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Injuries / metabolism*
  • Brain Injuries / psychology
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Male
  • Memory, Short-Term / physiology*
  • Phosphorylation
  • Prefrontal Cortex / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology


  • Cyclic AMP-Dependent Protein Kinases