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Compartmentalized versus global synaptic plasticity on dendrites controlled by experience.

ABSTRACT: Synapses in the brain are continuously modified by experience, but the mechanisms are poorly understood. In vitro and theoretical studies suggest threshold-lowering interactions between nearby synapses that favor clustering of synaptic plasticity within a dendritic branch. Here, a fluorescently tagged AMPA receptor-based optical approach was developed permitting detection of single-synapse plasticity in mouse cortex. Sensory experience preferentially produced synaptic potentiation onto nearby dendritic synapses. Such clustering was significantly reduced by expression of a phospho-mutant AMPA receptor that is insensitive to threshold-lowering modulation for plasticity-driven synaptic incorporation. In contrast to experience, sensory deprivation caused homeostatic synaptic enhancement globally on dendrites. Clustered synaptic potentiation produced by experience could bind behaviorally relevant information onto dendritic subcompartments; global synaptic upscaling by deprivation could equally sensitize all dendritic regions for future synaptic input.

SUBMITTER: Makino H

PROVIDER: S-EPMC3310180 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Compartmentalized versus global synaptic plasticity on dendrites controlled by experience.

Makino Hiroshi H Malinow Roberto R

Neuron 20111201 6

Synapses in the brain are continuously modified by experience, but the mechanisms are poorly understood. In vitro and theoretical studies suggest threshold-lowering interactions between nearby synapses that favor clustering of synaptic plasticity within a dendritic branch. Here, a fluorescently tagged AMPA receptor-based optical approach was developed permitting detection of single-synapse plasticity in mouse cortex. Sensory experience preferentially produced synaptic potentiation onto nearby de ...[more]

PMID: 22196335

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Project description:UnlabelledAlterations 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.Significance statementNeurons 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

Compartmentalized versus global synaptic plasticity on dendrites controlled by experience.

Publications

Compartmentalized versus global synaptic plasticity on dendrites controlled by experience.

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