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 Nishi

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Rationale: 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). Objectives: We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1065-1079
Number of pages15
JournalPsychopharmacology
Volume219
Issue number4
DOIs
StatePublished - Feb 2012

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Type 4 Cyclic Nucleotide Phosphodiesterase
Rolipram
Dopamine D1 Receptors
Frontal Lobe
Schizophrenia
Pyramidal Cells
Phosphorylation
Cognition
Phosphodiesterase 4 Inhibitors
Sensory Gating
Neurons
Neurobehavioral Manifestations
Aptitude
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Second Messenger Systems
Enzymes
Prefrontal Cortex
Synaptic Transmission
Antipsychotic Agents

Keywords

  • DARPP-32
  • Frontal cortex
  • PDE4
  • PKA
  • Prepulse inhibition
  • Rolipram

ASJC Scopus subject areas

  • Pharmacology

Cite this

Kuroiwa, M., Snyder, G. L., Shuto, T., Fukuda, A., Yanagawa, Y., Benavides, D. R., ... Nishi, A. (2012). Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology, 219(4), 1065-1079. https://doi.org/10.1007/s00213-011-2436-8

Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. / Kuroiwa, Mahomi; Snyder, Gretchen L.; Shuto, Takahide; Fukuda, Atsuo; Yanagawa, Yuchio; Benavides, David R.; Nairn, Angus C.; Bibb, James A.; Greengard, Paul; Nishi, Akinori.

In: Psychopharmacology, Vol. 219, No. 4, 02.2012, p. 1065-1079.

Research output: Contribution to journalArticle

Kuroiwa, M, Snyder, GL, Shuto, T, Fukuda, A, Yanagawa, Y, Benavides, DR, Nairn, AC, Bibb, JA, Greengard, P & Nishi, A 2012, 'Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex', Psychopharmacology, vol. 219, no. 4, pp. 1065-1079. https://doi.org/10.1007/s00213-011-2436-8
Kuroiwa, Mahomi ; Snyder, Gretchen L. ; Shuto, Takahide ; Fukuda, Atsuo ; Yanagawa, Yuchio ; Benavides, David R. ; Nairn, Angus C. ; Bibb, James A. ; Greengard, Paul ; Nishi, Akinori. / Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. In: Psychopharmacology. 2012 ; Vol. 219, No. 4. pp. 1065-1079.
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abstract = "Rationale: 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). Objectives: We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4. Results: 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. Conclusions: 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.",
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AU - Kuroiwa, Mahomi

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AU - Shuto, Takahide

AU - Fukuda, Atsuo

AU - Yanagawa, Yuchio

AU - Benavides, David R.

AU - Nairn, Angus C.

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AB - Rationale: 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). Objectives: We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4. Results: 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. Conclusions: 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.

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KW - Prepulse inhibition

KW - Rolipram

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