A negative allosteric modulator of PDE4D enhances learning after traumatic brain injury

David J. Titus, Nicole M. Wilson, Oscar Alcazar, Dale A. Calixte, W. Dalton Dietrich, Mark E. Gurney, Coleen M. Atkins

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Traumatic brain injury (TBI) significantly decreases cyclic AMP (cAMP) signaling which produces long-term synaptic plasticity deficits and chronic learning and memory impairments. Phosphodiesterase 4 (PDE4) is a major family of cAMP hydrolyzing enzymes in the brain and of the four PDE4 subtypes, PDE4D in particular has been found to be involved in memory formation. Although most PDE4 inhibitors target all PDE4 subtypes, PDE4D can be targeted with a selective, negative allosteric modulator, D159687. In this study, we hypothesized that treating animals with D159687 could reverse the cognitive deficits caused by TBI. To test this hypothesis, adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. After 3 months of recovery, animals were treated with D159687 (0.3 mg/kg, intraperitoneally) at 30 min prior to cue and contextual fear conditioning, acquisition in the water maze or during a spatial working memory task. Treatment with D159687 had no significant effect on these behavioral tasks in non-injured, sham animals, but did reverse the learning and memory deficits in chronic TBI animals. Assessment of hippocampal slices at 3 months post-TBI revealed that D159687 reversed both the depression in basal synaptic transmission in area CA1 as well as the late-phase of long-term potentiation. These results demonstrate that a negative allosteric modulator of PDE4D may be a potential therapeutic to improve chronic cognitive dysfunction following TBI.

Original languageEnglish (US)
Pages (from-to)38-49
Number of pages12
JournalNeurobiology of Learning and Memory
Volume148
DOIs
StatePublished - Feb 2018
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by the National Institutes of Health / National Institute of Neurological Disorders and Stroke (R01 NS069721 to C.M.A., R01 NS056072 to C.M.A. and W.D.D. and R44 MH091791 to M.E.G.) and The Miami Project to Cure Paralysis. We thank Concepcion Furones, Jonathan Mendoza, Rosmery Santos and Kevin Sikah for technical support.

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • Cognition
  • Fluid Percussion Injury
  • Hippocampus
  • Memory
  • Phosphodiesterase
  • Traumatic brain injury

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