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 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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Robin J
RJ
Kleiman
Douglas S
DS
Chapin
Curt
C
Christoffersen
Jody
J
Freeman
Kari R
KR
Fonseca
Kieran F
KF
Geoghegan
Sarah
S
Grimwood
Victor
V
Guanowsky
Mihály
M
Hajós
John F
JF
Harms
Christopher J
CJ
Helal
William E
WE
Hoffmann
Geralyn P
GP
Kocan
Mark J
MJ
Majchrzak
Dina
D
McGinnis
Stafford
S
McLean
Frank S
FS
Menniti
Fredrick
F
Nelson
Robin
R
Roof
Anne W
AW
Schmidt
Patricia A
PA
Seymour
Diane T
DT
Stephenson
Francis David
FD
Tingley
Michelle
M
Vanase-Frawley
Patrick R
PR
Verhoest
Christopher J
CJ
Schmidt
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D055139:Sensory Gating / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D018678:Cholinergic Agents; D018377:Neurotransmitter Agents; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP