Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior.

Graeme B Bolger,Thomas Van Groen,Lisa High Mitchell Smoot

doi:10.3390/ijms21165704

Graeme B Bolger, Thomas Van Groen + Show 1 more

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https://doi.org/10.3390/ijms21165704

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Abstract

PDE4 cyclic nucleotide phosphodiesterases reduce 3′, 5′ cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins β-arrestin2 and RACK1, regulators of β2-adrenergic and other signal transduction pathways. Mutations in PDE4D in humans predispose to acrodysostosis, associated with cognitive and behavioral deficits. To target PDE4D5, we developed mice that express a PDE4D5-D556A dominant-negative transgene in the brain. Male transgenic mice demonstrated significant deficits in hippocampus-dependent spatial learning, as assayed in the Morris water maze. In contrast, associative learning, as assayed in a fear conditioning assay, appeared to be unaffected. Male transgenic mice showed augmented activity in prolonged (2 h) open field testing, while female transgenic mice showed reduced activity in the same assay. Transgenic mice showed no demonstrable abnormalities in prepulse inhibition. There was also no detectable difference in anxiety-like behavior, as measured in the elevated plus-maze. These data support the use of a dominant-negative approach to the study of PDE4D5 function in the CNS and specifically in learning and memory.

Highlights

IntroductionSelective inhibitors of the PDE4, 30 , 50 -cAMP-specific phosphodiesterases have proven cognition-enhancing and antidepressant properties in humans [1,2,3,4,5,6,7,8,9,10,11,12] and rodents [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48].PDE4-selective inhibitors are exploited therapeutically for their anti-inflammatory, immunomodulatory and smooth-muscle relaxant activities (for reviews, see [49,50,51])
The PDE4D5-D556A transgene was inherited at the expected Mendelian frequency, showing that the transgene did not produce toxicity or affect fetal viability
PDE4D5-D556A transgenic mice were grossly indistinguishable from wild-type littermates and commercially available C57BL/6J mice

Summary

Introduction

Selective inhibitors of the PDE4, 30 , 50 -cAMP-specific phosphodiesterases have proven cognition-enhancing and antidepressant properties in humans [1,2,3,4,5,6,7,8,9,10,11,12] and rodents [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48].PDE4-selective inhibitors are exploited therapeutically for their anti-inflammatory, immunomodulatory and smooth-muscle relaxant activities (for reviews, see [49,50,51]). A number of PDE4-selective inhibitors are under development for CNS indications, including depression and as enhancers of learning and memory [9,10,11,12,45,46,47,48,57,58,59,60,61,62,63]. PDE4-selective inhibitors inhibit the enzymatic hydrolysis of cAMP and thereby increase its levels in cells. One of their major effects is to activate cAMP-dependent protein kinase (PKA) and thereby stimulate the phosphorylation of its physiological substrates, including the cyclic nucleotide response

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