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A presynaptic role for FMRP during protein synthesis-dependent long-term plasticity in Aplysia.

ABSTRACT: Loss of the Fragile X mental retardation protein (FMRP) is associated with presumed postsynaptic deficits in mouse models of Fragile X syndrome. However, the possible presynaptic roles of FMRP in learning-related plasticity have received little attention. As a result, the mechanisms whereby FMRP influences synaptic function remain poorly understood. To investigate the cellular locus of the effects of FMRP on synaptic plasticity, we cloned the Aplysia homolog of FMRP and find it to be highly expressed in neurons. By selectively down-regulating FMRP in individual Aplysia neurons at the sensory-to-motor neuron synapse reconstituted in co-cultures, we demonstrate that FMRP functions both pre- and postsynaptically to constrain the expression of long-term synaptic depression induced by repeated pulses of FMRF-amide. In contrast, FMRP has little to no effect on long-term synaptic facilitation induced by repeated pulses of serotonin. Since other components of signaling pathways involved in plasticity appear to be conserved between Aplysia and mammalian neurons, our findings suggest that FMRP can participate in both pre- and postsynaptic regulation of enduring synaptic plasticity that underlies the storage of certain types of long-term memory.

SUBMITTER: Till SM

PROVIDER: S-EPMC3023967 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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A presynaptic role for FMRP during protein synthesis-dependent long-term plasticity in Aplysia.

Till Sally M SM Li Hsiu-Ling HL Miniaci Maria Concetta MC Kandel Eric R ER Choi Yun-Beom YB

Learning & memory (Cold Spring Harbor, N.Y.) 20101221 1

Loss of the Fragile X mental retardation protein (FMRP) is associated with presumed postsynaptic deficits in mouse models of Fragile X syndrome. However, the possible presynaptic roles of FMRP in learning-related plasticity have received little attention. As a result, the mechanisms whereby FMRP influences synaptic function remain poorly understood. To investigate the cellular locus of the effects of FMRP on synaptic plasticity, we cloned the Aplysia homolog of FMRP and find it to be highly expr ...[more]

PMID: 21177378

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Project description:Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood. Here we demonstrate that a nontelomeric isoform of telomere repeat-binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity. TRF2-S interacts directly with target mRNAs to facilitate their axonal delivery. The process is antagonized by fragile X mental retardation protein (FMRP). Distinct from the current RNA-binding model of FMRP, we show that FMRP occupies the GAR domain of TRF2-S protein to block the assembly of TRF2-S-mRNA complexes. Overexpressing TRF2-S and silencing FMRP promotes mRNA entry to axons, and enhances axonal outgrowth and neurotransmitter release from presynaptic terminals. Our findings suggest a pivotal role for TRF2-S in an axonal mRNA localization pathway that enhances axon outgrowth and neurotransmitter release. RNA immunoprecipitated samples using either anti-rat TRF2-S or rabbit IgG antibodies were used to generate biotin-labeled RNA using the Illumina Total Prep RNA Amplification Kit (Ambion), which was hybridized to Illumina's rat Ref-12 Expression BeadChips (Illumina, San Diego, CA), containing 22,523 well-annotated RefSeq transcripts with ~30-fold redundancy. The arrays were scanned using an Illumina BeadStation 500X Genetic Analysis Systems scanner and the image data extracted using Illumina BeadStudio software, version 1.5, normalized by Z-score transformation and used to calculate differences in signal intensities. Significant values were calculated from two groups of independent experiments, using a two-tailed Z-test with P < 0.05, a false discovery rate <0.30, a z ratio absolute value not less than 1.5, and an average signal intensity not less than zero. The results also had to pass the filtering and one-way independent ANOVA test by sample groups less than 0.05, and detection p-value for any probe in the comparison group less than 0.02.

Dataset Information

A presynaptic role for FMRP during protein synthesis-dependent long-term plasticity in Aplysia.

Publications

A presynaptic role for FMRP during protein synthesis-dependent long-term plasticity in Aplysia.

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