Longevity, enhanced memory, and altered density of dendritic spines in hippocampal CA3 and dentate gyrus after hemizygous deletion of Pde2a in mice.

Autor: Baumgärtel K; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA.; Amplio Consulting LLC5284 Dawes St, San Diego, CA, 92109, USA., Broadbent NJ; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Su H; Neurophysiology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Masatsugu B; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Maruyama KP; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Johnson RW; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Green AL; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Hornberger DK; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Petroski R; Neurophysiology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Scott R; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA., Peters M; Target Discovery & Behavioral Pharmacology, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA, 92131, USA. dr.marco.peters@gmail.com.; Center for the Neurobiology of Learning and Memory, University of California Irvine, Qureshey Research Laboratory, Irvine, CA, 92697, USA. dr.marco.peters@gmail.com.
Jazyk: angličtina
Zdroj: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2024 Nov 27. Date of Electronic Publication: 2024 Nov 27.
DOI: 10.1038/s41386-024-02031-w
Abstrakt: Studies using acute or subchronic pharmacological inhibition of phosphodiesterase 2 A (PDE2A) have led to its proposal as a target for treatment of cognitive deficits associated with neuropsychiatric and neurodegenerative disease. However, the impact of continuous inhibition of PDE2A on memory is unknown. Moreover, the neuroanatomical regions mediating memory enhancement have not been categorically identified. To address these open questions, we studied knockout mice and hippocampus restricted manipulations. Pde2a heterozygous knockout mice are viable with no gross histological abnormalities. The mice exhibit enhanced spatial and object recognition memory that is independent of anxiolytic effects and is paralleled by increased density of dendritic mushroom and thin spines in hippocampal CA3 and dentate gyrus in adult mice. In CA1, subtle alterations in spine density were seen, while theta-burst LTP and paired-pulse facilitation were normal. Spatial memory enhancement persists in aged Pde2a heterozygous knockout mice, and to our surprise these mice live significantly longer than wild-type littermate controls. In summary, we provide evidence that life-long reduction of PDE2A expression promotes spine formation and maturation, exerts beneficial effects on memory, and increases lifespan.
Competing Interests: Competing interests: All authors are past employees of Dart Neuroscience, LLC. MP has consulted for companies involved with the development of PDE inhibitors, including Dart Neuroscience, LLC. All other authors declare no financial conflict of interest.
(© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)
Databáze: MEDLINE
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