Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo
Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the c...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 341; no. 2; pp. 396 - 409 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
01.05.2012
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Abstract | Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems. |
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AbstractList | Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems. |
Author | Roof, Robin McGinnis, Dina Kleiman, Robin J Kocan, Geralyn P Nelson, Fredrick Stephenson, Diane T Tingley, Francis David Verhoest, Patrick R Chapin, Douglas S Menniti, Frank S Christoffersen, Curt Helal, Christopher J Vanase-Frawley, Michelle Guanowsky, Victor Geoghegan, Kieran F Hajós, Mihály Grimwood, Sarah Majchrzak, Mark J Hoffmann, William E Harms, John F Seymour, Patricia A Freeman, Jody Fonseca, Kari R McLean, Stafford Schmidt, Christopher J Schmidt, Anne W |
Author_xml | – sequence: 1 givenname: Robin J surname: Kleiman fullname: Kleiman, Robin J email: kleimanrj@gmail.com organization: SystaMedic Inc., 1084 Shennecossett Drive, Groton, CT 06340, USA. kleimanrj@gmail.com – sequence: 2 givenname: Douglas S surname: Chapin fullname: Chapin, Douglas S – sequence: 3 givenname: Curt surname: Christoffersen fullname: Christoffersen, Curt – sequence: 4 givenname: Jody surname: Freeman fullname: Freeman, Jody – sequence: 5 givenname: Kari R surname: Fonseca fullname: Fonseca, Kari R – sequence: 6 givenname: Kieran F surname: Geoghegan fullname: Geoghegan, Kieran F – sequence: 7 givenname: Sarah surname: Grimwood fullname: Grimwood, Sarah – sequence: 8 givenname: Victor surname: Guanowsky fullname: Guanowsky, Victor – sequence: 9 givenname: Mihály surname: Hajós fullname: Hajós, Mihály – sequence: 10 givenname: John F surname: Harms fullname: Harms, John F – sequence: 11 givenname: Christopher J surname: Helal fullname: Helal, Christopher J – sequence: 12 givenname: William E surname: Hoffmann fullname: Hoffmann, William E – sequence: 13 givenname: Geralyn P surname: Kocan fullname: Kocan, Geralyn P – sequence: 14 givenname: Mark J surname: Majchrzak fullname: Majchrzak, Mark J – sequence: 15 givenname: Dina surname: McGinnis fullname: McGinnis, Dina – sequence: 16 givenname: Stafford surname: McLean fullname: McLean, Stafford – sequence: 17 givenname: Frank S surname: Menniti fullname: Menniti, Frank S – sequence: 18 givenname: Fredrick surname: Nelson fullname: Nelson, Fredrick – sequence: 19 givenname: Robin surname: Roof fullname: Roof, Robin – sequence: 20 givenname: Anne W surname: Schmidt fullname: Schmidt, Anne W – sequence: 21 givenname: Patricia A surname: Seymour fullname: Seymour, Patricia A – sequence: 22 givenname: Diane T surname: Stephenson fullname: Stephenson, Diane T – sequence: 23 givenname: Francis David surname: Tingley fullname: Tingley, Francis David – sequence: 24 givenname: Michelle surname: Vanase-Frawley fullname: Vanase-Frawley, Michelle – sequence: 25 givenname: Patrick R surname: Verhoest fullname: Verhoest, Patrick R – sequence: 26 givenname: Christopher J surname: Schmidt fullname: Schmidt, Christopher J |
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SubjectTerms | 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors 3',5'-Cyclic-AMP Phosphodiesterases - genetics 3',5'-Cyclic-AMP Phosphodiesterases - metabolism 3',5'-Cyclic-GMP Phosphodiesterases - metabolism Animals Avoidance Learning - drug effects Brain - drug effects Brain - metabolism Cholinergic Agents - pharmacology Cyclic GMP - metabolism Female Humans Macaca fascicularis Male Memory - drug effects Mice Mice, Inbred C57BL Motor Activity - drug effects Neurons - drug effects Neurons - metabolism Neurotransmitter Agents - pharmacology Phosphodiesterase Inhibitors - pharmacology Rats Rats, Long-Evans Rats, Wistar Sensory Gating - drug effects Stereotyped Behavior - drug effects Synaptic Transmission - drug effects |
Title | Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo |
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