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Endogenous amyloid-? is necessary for hippocampal synaptic plasticity and memory.

ABSTRACT: The goal of this study was to investigate the role of endogenous amyloid-? peptide (A?) in healthy brain.Long-term potentiation (LTP), a type of synaptic plasticity that is thought to be associated with learning and memory, was examined through extracellular field recordings from the CA1 region of hippocampal slices, whereas behavioral techniques were used to assess contextual fear memory and reference memory. Amyloid precursor protein (APP) expression was reduced through small interfering RNA (siRNA) technique.We found that both antirodent A? antibody and siRNA against murine APP reduced LTP as well as contextual fear memory and reference memory. These effects were rescued by the addition of human A???, suggesting that endogenously produced A? is needed for normal LTP and memory. Furthermore, the effect of endogenous A? on plasticity and memory was likely due to regulation of transmitter release, activation of ?7-containing nicotinic acetylcholine receptors, and A??? production.Endogenous A??? is a critical player in synaptic plasticity and memory within the normal central nervous system. This needs to be taken into consideration when designing therapies aiming at reducing A? levels to treat Alzheimer disease.

SUBMITTER: Puzzo D

PROVIDER: S-EPMC4071456 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory.

Puzzo Daniela D Privitera Lucia L Fa' Mauro M Staniszewski Agnieszka A Hashimoto Gakuji G Aziz Fahad F Sakurai Mikako M Ribe Elena M EM Troy Carol M CM Mercken Marc M Jung Sonia S SS Palmeri Agostino A Arancio Ottavio O

Annals of neurology 20110406 5

<h4>Objective</h4>The goal of this study was to investigate the role of endogenous amyloid-β peptide (Aβ) in healthy brain.<h4>Methods</h4>Long-term potentiation (LTP), a type of synaptic plasticity that is thought to be associated with learning and memory, was examined through extracellular field recordings from the CA1 region of hippocampal slices, whereas behavioral techniques were used to assess contextual fear memory and reference memory. Amyloid precursor protein (APP) expression was reduc ...[more]

PMID: 21472769

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Project description:Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling.Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The phosphodiesterase 4 (PDE4) family coordinates the degradation of cAMP, leading to the local attenuation of cAMP-dependent signaling pathways. Sleep deprivation leads to increased hippocampal expression of the PDE4A5 isoform. Here, we explored whether PDE4A5 overexpression mimics behavioral and synaptic plasticity phenotypes associated with sleep deprivation. Viral expression of PDE4A5 in hippocampal neurons impairs long-term potentiation and attenuates the formation of hippocampus-dependent long-term memories. Our findings suggest that PDE4A5 is a molecular constraint on cognitive processes and may contribute to the development of novel therapeutic approaches to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling.

Dataset Information

Endogenous amyloid-? is necessary for hippocampal synaptic plasticity and memory.

Publications

Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory.

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