Phosphodiesterase 4 Inhibition After Retrieval Switches the Memory Fate Favoring Extinction Instead of Reconsolidation

Overview

Journal Sci Rep

Specialty Science

Date 2023 Nov 22

PMID 37990053

Authors

Jeferson Machado Batista Sohn

Nathalie Carla Cardoso

Ana Maria Raymundi

Jos Prickaerts

Cristina Aparecida Jark Stern

Affiliations

Soon will be listed here.

Abstract

Phosphodiesterase 4 (PDE4), an enzyme expressed in the dorsal hippocampus (DH), hydrolyzes the cAMP, limiting the PKA-induced CREB phosphorylation (pCREB) and BDNF expression. Depending on the brain region, PKA and pCREB mediate reconsolidation or extinction, whereas BDNF is mainly related to extinction facilitation. The mechanisms underpinning the switch between reconsolidation and extinction are relatively unknown. Here, we tested the hypothesis that PDE4 might control these processes. We showed in Wistar rats submitted to contextual fear conditioning that PDE4 inhibition with roflumilast (ROF) within the DH, after a short retrieval, did not change freezing behavior after one day (TestA). After 10 days, the ROF-treated group significantly reduced the expression of freezing behavior. This effect depended on retrieval, Test A exposure, and reinstated after a remainder foot shock, suggesting an extinction facilitation. The ROF effect depended on PKA after retrieval or, protein synthesis after Test A. After retrieval, ROF treatment did not change the pCREB/CREB ratio in the DH. It enhanced proBDNF expression without changing pre-proBDNF or mature BDNF in the DH after Test A. The results suggest that the inhibition of PDE4 in the DH after a short retrieval changes the memory sensibility from reconsolidation to extinction via regulating proBDNF expression.

Citing Articles

Modulation of Second Messenger Signaling in the Brain Through PDE4 and PDE5 Inhibition: Therapeutic Implications for Neurological Disorders.

Park M, Yang H, Woo S, Kim D, Son D, Choi B Cells. 2025; 14(2.

PMID: 39851514 PMC: 11763391. DOI: 10.3390/cells14020086.

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