title: Inhibition of PDE2A, but not PDE9A, modulates presynaptic short-term plasticity measured by paired-pulse facilitation in the CA1 region of the hippocampus.
abstract: Phosphodiesterase (PDE) inhibitors are currently considered promising therapeutic targets for treatment of cognitive impairment in diseases such as Schizophrenia and Alzheimer's disease. Inhibitors of PDE2A and PDE9A have emerged as potential candidates shown to improve synaptic plasticity and memory function in animals. However, the functional relevance of their putative different localization in the neuron is not understood. Thus, this study aims at elucidating potential presynaptic effects of PDE2A inhibition in comparison to the inhibition of PDE9A. For this purpose, we used paired-pulse facilitation (PPF), a model of short-term synaptic plasticity related to presynaptic function. First, we performed a series of experiments to validate the model in acute rat hippocampal slices using several reference substances including calcium channel blockers, glutamatergic receptor antagonists, and GPCR agonists. Second, we analysed the effect of PDE2A and PDE9A inhibition and their role regulating the influence that the second messengers cAMP and cGMP exert on basal transmission. Our results show that the interplay between the adenylyl cyclase activator forskolin, the soluble guanylyl cyclase activator BAY 41-8543 and the PDE2A inhibitor PF-999 reveals a primarily presynaptic mechanism of action of PDE2A inhibition. On the contrary, inhibition of PDE9A did not alter PPF under similar conditions. In conclusion, these data provide new evidence supporting a role of PDE2A modulating short-term synaptic plasticity. Moreover, this function of PDE2A is suggested to rely on an active modulation of the cAMP hydrolysis as a response to changes in cGMP levels at the presynaptic level.
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach (Riss), 88397, Germany.
authors.forename: Diego
authors.initials: D
authors.lastname: Fernández-Fernández
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach (Riss), 88397, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Rosenbrock
authors.affiliation: Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach (Riss), 88397, Germany.
authors.forename: Katja S
authors.initials: KS
authors.lastname: Kroker
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D019256:Cadmium Chloride / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010069:Oxadiazoles / Q000493:pharmacokinetics; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C450679:BAY 41-8543; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D010069:Oxadiazoles; D011743:Pyrimidines; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D005576:Colforsin; D000242:Cyclic AMP; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517278:Pde2a protein, rat; D006152:Cyclic GMP; D019256:Cadmium Chloride; D000241:Adenosine
keywords: Alzheimer's disease; BAY 41-8543; PDE2A; PDE9A; hippocampus