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Homeostatic regulation of AMPA receptor expression at single hippocampal synapses.

ABSTRACT: Homeostatic synaptic response is an important measure in confining neuronal activity within a narrow physiological range. Whether or not homeostatic plasticity demonstrates synapse specificity, a key feature characteristic of Hebbian-type plasticity, is largely unknown. Here, we report that in cultured hippocampal neurons, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid subtype glutamate receptor (AMPAR) accumulation is increased selectively in chronically inhibited single synapses, whereas the neighboring normal synapses remain unaffected. This synapse-specific homeostatic regulation depends on the disparity of synaptic activity and is mediated by GluR2-lacking AMPARs and PI3-kinase signaling. These results demonstrate the existence of synaptic specificity and the crucial role of AMPAR-gated calcium in homeostatic plasticity in central neurons.

SUBMITTER: Hou Q

PROVIDER: S-EPMC2206612 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Homeostatic regulation of AMPA receptor expression at single hippocampal synapses.

Hou Qingming Q Zhang Dawei D Jarzylo Larissa L Huganir Richard L RL Man Heng-Ye HY

Proceedings of the National Academy of Sciences of the United States of America 20080103 2

Homeostatic synaptic response is an important measure in confining neuronal activity within a narrow physiological range. Whether or not homeostatic plasticity demonstrates synapse specificity, a key feature characteristic of Hebbian-type plasticity, is largely unknown. Here, we report that in cultured hippocampal neurons, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid subtype glutamate receptor (AMPAR) accumulation is increased selectively in chronically inhibited single synapses, wh ...[more]

PMID: 18174334

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Project description:Neuronal networks are subject to fluctuations in both the magnitude and frequency of inputs, requiring plasticity mechanisms to stabilize network activity. Homeostatic synaptic scaling is a form of synaptic plasticity that adjusts the strength of neuronal connections up or down in response to large changes in input. Although homeostatic plasticity requires changes in gene expression, there is only limited data describing the molecular changes associated with homeostatic scaling, focusing mostly on the expression mechanisms involving glutamate receptors. The fact that neuronal networks can be scaled up (in response to reduced activity) or down (in response to enhanced activity) provides a unique opportunity to examine the molecular and proteomic response to opposite ends of the phenotypic spectrum of synaptic plasticity. Here we first demonstrate that homeostatic scaling required protein synthesis. We then examined the plasticity-induced changes in the newly-synthesized neuronal proteome of neurons to identify the landscape of proteomic changes that contribute to opposing forms of homeostatic plasticity. Cultured rat hippocampal neurons (21 DIV) underwent homeostatic upscaling or downscaling (treatments with TTX and Bicucculine, respectively). We used BONCAT (BioOrthogonal Non-Canonical Amino acid Tagging) to metabolically label, capture and identify newly-synthesized proteins, detecting and analysing 5940 newly-synthesized proteins using liquid chromatography-coupled tandem mass spectrometry and label-free quantitation. Neither up- or down-scaling produced changes in the number of different proteins translated. Rather, our findings indicate that synaptic up- and down-scaling elicit opposing translational regulation of several molecular pathways, producing targeted adjustments in the neuronal proteome. We detected ~ 300 differentially regulated proteins involved in neurite outgrowth, reorganization of nerve terminals, axon guidance and targeting, neurotransmitter transport, filopodia assembly, excitatory synapses and glutamate receptor complexes. These proteins include well-characterized mediators of synaptic plasticity, e.g. the ionotropic glutamate receptor complex that is down-regulated during down-scaling and coordinately upregulated during upscaling. We also identified differentially regulated proteins that in addition to their regulation in homeostatic plasticity, are also associated with multiple diseases and disorders, including intellectual disability, schizophrenia, epilepsy, and Parkinson’s disease.

Dataset Information

Homeostatic regulation of AMPA receptor expression at single hippocampal synapses.

Publications

Homeostatic regulation of AMPA receptor expression at single hippocampal synapses.

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