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

被引:51
作者
Kuroiwa, Mahomi [1 ,2 ]
Snyder, Gretchen L. [3 ]
Shuto, Takahide [1 ,2 ]
Fukuda, Atsuo [4 ]
Yanagawa, Yuchio [2 ,5 ]
Benavides, David R. [6 ]
Nairn, Angus C. [7 ,8 ]
Bibb, James A. [6 ]
Greengard, Paul [8 ]
Nishi, Akinori [1 ,2 ,8 ]
机构
[1] Kurume Univ, Sch Med, Dept Pharmacol, Kurume, Fukuoka 8300011, Japan
[2] Japan Sci & Technol Agcy, CREST, Tokyo 1020075, Japan
[3] Intracellular Therapies Inc, New York, NY 10032 USA
[4] Hamamatsu Univ Sch Med, Dept Physiol, Hamamatsu, Shizuoka 4313192, Japan
[5] Gunma Univ, Grad Sch Med, Dept Genet & Behav Neurosci, Maebashi, Gunma 3718511, Japan
[6] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA
[7] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA
[8] Rockefeller Univ, Lab Mol & Cellular Neurosci, New York, NY 10021 USA
基金
日本学术振兴会; 美国国家卫生研究院;
关键词
PDE4; DARPP-32; PKA; Frontal cortex; Prepulse inhibition; Rolipram; CAMP-SPECIFIC PHOSPHODIESTERASE; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; AMP-REGULATED PHOSPHOPROTEIN; DEPENDENT PROTEIN-KINASE; KNOCK-OUT MICE; PREPULSE INHIBITION; PREFRONTAL CORTEX; D-1; RECEPTOR; TYROSINE-HYDROXYLASE; PSYCHIATRIC-ILLNESS;
D O I
10.1007/s00213-011-2436-8
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1065 / 1079
页数:15
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