, Volume 219, Issue 4, pp 1065–1079 | Cite as

Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex

  • Mahomi Kuroiwa
  • Gretchen L. Snyder
  • Takahide Shuto
  • Atsuo Fukuda
  • Yuchio Yanagawa
  • David R. Benavides
  • Angus C. Nairn
  • James A. Bibb
  • Paul Greengard
  • Akinori NishiEmail author
Original Investigation



Alteration of dopamine neurotransmission in the prefrontal cortex, especially hypofunction of dopamine D1 receptors, contributes to psychotic symptoms and cognitive deficit in schizophrenia. D1 receptors signal through the cAMP/PKA second messenger cascade, which is modulated by phosphodiesterase (PDE) enzymes that hydrolyze and inactivate cyclic nucleotides. Though several PDEs are expressed in cortical neurons, the PDE4 enzyme family (PDE4A-D) has been implicated in the control of cognitive function. The best studied isoform, PDE4B, interacts with a schizophrenia susceptibility factor, disrupted in schizophrenia 1 (DISC1).


We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4.


Inhibition of PDE4 by rolipram induced activation of cAMP/PKA signaling in cortical slices and in vivo, leading to the phosphorylation of DARPP-32 and other postsynaptic and presynaptic PKA-substrates. Rolipram also enhanced DARPP-32 phosphorylation invoked by D1 receptor activation. Immunohistochemical studies demonstrated PDE4A, PDE4B, and PDE4D expression in DARPP-32-positive neurons in layer VI of frontal cortex, most likely in D1 receptor-positive, glutamatergic corticothalamic pyramidal neurons. Furthermore, the ability of rolipram treatment to improve the performance of mice in a sensorimotor gating test was DARPP-32-dependent.


PDE4, which is co-expressed with DARPP-32 in D1 receptor-positive cortical pyramidal neurons in layer VI, modulates the level of D1 receptor signaling and DARPP-32 phosphorylation in the frontal cortex, likely influencing cognitive function. These biochemical and behavioral actions of PDE4 inhibitors may contribute to the hypothesized antipsychotic actions of this class of compounds.


PDE4 DARPP-32 PKA Frontal cortex Prepulse inhibition Rolipram 



This research was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (18300128 to A.N.) and grants from the US National Institutes of Health to G.L.S. (MH067488), J.A.B. (MH79710, MH083711, and DA016672), and P.G. and A.C.N. (MH 090963 and DA10044); the Michael Stern Parkinson's Research Foundation (to P.G.); and the Department of Defense (DOD/USAMRAA W81XWH-09-1-402 and W81XWH-10-1-0640 to P.G.). G.L.S. was supported by funds from Intra-Cellular Therapies Inc. G.L.S. receives additional support from the United States Army Medical Research and Materiel Command NETRP Program (DAMD 17-03-2-0019, W81XWH-05-1-0400, and W81XWH-06-C-0013 to Intra-Cellular Therapies Inc). The authors thank Yukako Terasaki, Keiko Fujisaki, Michiko Sakamoto, Minal Rana, Tiffany Tsui, and Tomonori Furukawa for excellent technical assistance.

Conflicts of interest


Supplementary material

213_2011_2436_MOESM1_ESM.doc (5 mb)
Online Resource 1 Expression of PDE4 subtypes in the cortex. Double immunostaining of mouse cortical tissues with DARPP-32 and PDE4A (a), PDE4C (b), or PDE4D (c, d) antibodies. High magnification pictures of cingulate cortex: area 1 for PDE4A (a, inset) and PDE4D (d) staining are shown. Scale bars, 50 mm for ac and 10 mm for a inset and d (DOC 5094 kb)


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Mahomi Kuroiwa
    • 1
    • 2
  • Gretchen L. Snyder
    • 3
  • Takahide Shuto
    • 1
    • 2
  • Atsuo Fukuda
    • 4
  • Yuchio Yanagawa
    • 2
    • 5
  • David R. Benavides
    • 6
  • Angus C. Nairn
    • 7
    • 8
  • James A. Bibb
    • 6
  • Paul Greengard
    • 8
  • Akinori Nishi
    • 1
    • 2
    • 8
    Email author
  1. 1.Department of PharmacologyKurume University School of MedicineKurumeJapan
  2. 2.Japan Science of Technology AgencyCRESTTokyoJapan
  3. 3.Intra-Cellular Therapies, IncNew YorkUSA
  4. 4.Department of PhysiologyHamamatsu University School of MedicineHamamatsuJapan
  5. 5.Department of Genetic and Behavioral NeuroscienceGunma University Graduate School of MedicineMaebashiJapan
  6. 6.Department of PsychiatryThe University of Texas Southwestern Medical CenterDallasUSA
  7. 7.Department of PsychiatryYale University School of MedicineNew HavenUSA
  8. 8.Laboratory of Molecular and Cellular NeuroscienceThe Rockefeller UniversityNew YorkUSA

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