Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex
- 729 Downloads
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.
KeywordsPDE4 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
- Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME (2010) Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 28:63–70PubMedCrossRefGoogle Scholar
- Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54:387–402PubMedCrossRefGoogle Scholar
- Ehrman LA, Williams MT, Schaefer TL, Gudelsky GA, Reed TM, Fienberg AA, Greengard P, Vorhees CV (2006) Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice. Genes Brain Behav 5:540–551PubMedCrossRefGoogle Scholar
- Fienberg AA, Hiroi N, Mermelstein P, Song W-J, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller D, Cole D, Corbett R, Haile C, Cooper D, Onn S, Grace AA, Ouimet C, White FJ, Hyman SE, Surmeier DJ, Girault JA, Nestler E, Greengard P (1998) DARPP-32, regulator of the efficacy of dopaminergic neurotransmission. Science 281:838–842PubMedCrossRefGoogle Scholar
- Fiumara F, Giovedi S, Menegon A, Milanese C, Merlo D, Montarolo PG, Valtorta F, Benfenati F, Ghirardi M (2004) Phosphorylation by cAMP-dependent protein kinase is essential for synapsin-induced enhancement of neurotransmitter release in invertebrate neurons. J Cell Sci 117:5145–5154PubMedCrossRefGoogle Scholar
- Hoffmann R, Wilkinson IR, McCallum JF, Engels P, Houslay MD (1998) cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Biochem J 333(Pt 1):139–149PubMedGoogle Scholar
- MacKenzie SJ, Baillie GS, McPhee I, MacKenzie C, Seamons R, McSorley T, Millen J, Beard MB, van Heeke G, Houslay MD (2002) Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in Upstream Conserved Region 1 (UCR1). Br J Pharmacol 136:421–433PubMedCrossRefGoogle Scholar
- McCahill AC, Huston E, Li X, Houslay MD (2008) PDE4 associates with different scaffolding proteins: modulating interactions as treatment for certain diseases. Handb Exp Pharmacol: 125–66Google Scholar
- McPhee I, Yarwood SJ, Scotland G, Huston E, Beard MB, Ross AH, Houslay ES, Houslay MD (1999) Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B. Consequences for rolipram inhibition. J Biol Chem 274:11796–11810PubMedCrossRefGoogle Scholar
- Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310:1187–1191PubMedCrossRefGoogle Scholar
- Ouimet CC, Miller PE, Hemmings HC Jr, Walaas SI, Greengard P (1984) DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J Neurosci 4:114–124Google Scholar
- Tanda K, Nishi A, Matsuo N, Nakanishi K, Yamasaki N, Sugimoto T, Toyama K, Takao K, Miyakawa T (2009) Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice. Mol Brain 2:19PubMedCrossRefGoogle Scholar