Mice Lacking the cAMP Effector Protein POPDC1 Show Enhanced Hippocampal Synaptic Plasticity

Mahesh Shivarama Shetty; Laurence Ris; Schindler Rfr; Keiko Mizuno; Fedele L; Giese Kp; Thomas Brand; Ted Abel

doi:10.1093/cercor/bhab426

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Mice Lacking the cAMP Effector Protein POPDC1 Show Enhanced Hippocampal Synaptic Plasticity

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Mice Lacking the cAMP Effector Protein POPDC1 Show Enhanced Hippocampal Synaptic Plasticity

Mahesh Shivarama Shetty, Laurence Ris, Schindler Rfr, Keiko Mizuno, Fedele L, Giese Kp, Thomas Brand and Ted Abel

Cerebral cortex (New York, N.Y. 1991), Vol.32(16), pp.3457-3471

08/15/2022

DOI: 10.1093/cercor/bhab426

PMCID: PMC9376866

PMID: 34937090

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Abstract

Abstract Extensive research has uncovered diverse forms of synaptic plasticity and an array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cyclic 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent signaling pathways are crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of Popeye domain-containing protein 1 (POPDC1) (or blood vessel epicardial substance (BVES)), a cAMP effector protein, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as protein kinase A (PKA) and exchange factor directly activated by cAMP, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains, suggesting that POPDC1 may have an unique role in cAMP-mediated signaling. Our results show that Popdc1 is widely expressed in various brain regions including the hippocampus. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit PKA-dependent enhancement in CA1 long-term potentiation (LTP) in response to weaker stimulation paradigms, which in slices from wild-type mice induce only transient LTP. Loss of POPDC1, while not affecting basal transmission or input-specificity of LTP, results in altered response during high-frequency stimulation. Popdc1 KO mice also show enhanced forskolin-induced potentiation. Overall, these findings reveal POPDC1 as a novel negative regulator of hippocampal synaptic plasticity and, together with recent evidence for its interaction with phosphodiesterases (PDEs), suggest that POPDC1 is involved in modulating activity-dependent local cAMP–PKA–PDE signaling.

Neuroscience

Signal Transduction

Chemistry

Effector

Hippocampal formation

Long-term potentiation

Phosphodiesterase

Stimulation

Synaptic plasticity

Wild type

Details

Title: Subtitle: Mice Lacking the cAMP Effector Protein POPDC1 Show Enhanced Hippocampal Synaptic Plasticity
Creators: Mahesh Shivarama Shetty
Laurence Ris - University of Mons
Schindler Rfr
Keiko Mizuno - King's College London
Fedele L
Giese Kp
Thomas Brand - Imperial College London
Ted Abel - University of Iowa
Resource Type: Journal article
Publication Details: Cerebral cortex (New York, N.Y. 1991), Vol.32(16), pp.3457-3471
DOI: 10.1093/cercor/bhab426
PMID: 34937090
PMCID: PMC9376866
NLM abbreviation: Cereb Cortex
ISSN: 1460-2199
eISSN: 1460-2199
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 MH 117964; DOI: 10.13039/501100007155, name: Medical Research Council, award: MR/J010383/1; DOI: 10.13039/501100000274, name: British Heart Foundation, award: PG14/46/3091, PG19/13/34247; name: Belgian Queen Elisabeth Medical Foundation
Language: English
Electronic publication date: 12/23/2021
Date published: 08/15/2022
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984530268402771

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