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trafficking and dendritic protein synthesis to synaptic ..

studies linking synaptic plasticity to dendritic protein synthesis and mRNA ..

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The roles of protein expression in synaptic plasticity and memory ..

Structural and functional changes that take place in dendritic spines during LTP of synaptic transmission are widely thought to participate in memory formation. Reorganization of the actin cytoskeleton is a necessary step for LTP consolidation in hippocampus (; ; ). Similarly, dendritic protein synthesis has been shown to be required for certain forms of synaptic plasticity (; ; ). BDNF plays a major role in activity-dependent synaptic modifications, through stimulation of both actin polymerization and mammalian target of rapamycin (mTOR)-mediated protein translation (; ). However, the temporal and spatial relationships between these two important events are not yet fully understood.

a protein long implicated in synaptic plasticity and memory storage, ..

In conclusion, the present study shed new light into the mechanisms regulating activity-dependent synaptic plasticity in hippocampus. RhoA is rapidly and locally synthesized and degraded in response to synaptic stimulation, resulting in reorganization of actin cytoskeleton in dendritic spines during LTP. This mechanism provides a novel link between dendritic protein synthesis and actin polymerization, two major events required for hippocampal LTP and memory consolidation.

Glossary | Linus Pauling Institute | Oregon State University

Emerging evidence indicates that calpains are key regulators of synaptic plasticity as well as neurodegeneration (; ). Calpain-mediated spectrin truncation has been implicated in reorganization of the actin cytoskeleton during LTP (; ). Our results further demonstrate a novel role for calpains in regulating structural synaptic plasticity by controlling RhoA protein availability. Treatment with the specific calpain-1 inhibitor rapidly enhanced RhoA levels and stimulated actin polymerization in a ROCK-sensitive manner, indicating that RhoA upregulation is sufficient to stimulate actin cytoskeletal dynamics. Interestingly, calpain-1 knock-out mice exhibit increased levels of RhoA and enhanced platelet spreading (). Therefore, it is tempting to speculate that hippocampal neurons from these mice might have higher levels of spine F-actin and increase spine size, given the role of RhoA/ROCK signaling in spine growth (; ). However, this might not be the case, as opposite effects on dendritic spine morphology were found following overexpression of constitutively active RhoA ().

Calpain was involved in both the synthesis and degradation of RhoA, with calpain-2 activation stimulating RhoA synthesis, whereas calpain-1 activation-mediated RhoA degradation (). The opposite roles of calpain-1 and calpain-2 in BDNF-mediated RhoA degradation and synthesis are similar to what we recently reported for BDNF-mediated changes in SCOP and are related to the recently identified function of calpain-2 in the regulation of BDNF-elicited mTOR-dependent dendritic protein synthesis through calpain-2-mediated PTEN degradation (). Our results are also consistent with previous studies showing that RhoA is a calpain-1 substrate both in vivo and in vitro (; ). The fact that calpain-2 was also able to cleave RhoA in isolated brain membranes (but not in slices or synaptoneurosomes) suggests that the in situ selectivity of calpain-1 toward RhoA might be related to a specific subcellular localization and/or association of calpain-1 with specific protein scaffold complexes. In support of this notion, we recently reported that calpain-1 and -2 are specifically activated by synaptic and extrasynaptic NMDA receptors, respectively, to oppositely regulate neuronal fate (). In , we propose a model in which BDNF stimulation triggers rapid dendritic translation of RhoA through calpain-2-mediated PTEN truncation and the resulting stimulation of mTOR-dependent protein synthesis. Newly synthesized RhoA proteins would be transported to dendritic spines, where they would stimulate reorganization of the actin cytoskeleton through ROCK-mediated cofilin phosphorylation, and inactivation. In parallel, spine RhoA would be degraded by calpain-1.

Biochemistry of Neurotransmitters and Nerve Transmission

We used intrahippocampal injections of asODN directed against the translation initiation site of RhoA to specifically block de novo RhoA synthesis in dendrites without affecting basal levels of the protein. This approach has been previously used to successfully block synthesis of another protein involved in synaptic plasticity, namely, Arc (; ). In those studies, the authors showed that intrahippocampal injections of Arc asODN into the dentate gyrus rapidly reversed actin dynamics, LTP consolidation, and spatial memory. Another study reported impaired LTP and memory consolidation in knock-out mice lacking the dendritic targeting signal of CaMKII mRNA (). In the present work, we identified another protein, RhoA, whose translation is critical for hippocampal synaptic plasticity. Interestingly, RhoA asODN increased paired-pulse facilitation compared with scrambled ODN, suggesting an additional role for RhoA synthesis in presynaptic plasticity. These data are consistent with the previously reported involvement of RhoA in neurotransmitter release (). Overall, both presynaptically and postsynaptically located RhoA contributes to its effects on LTP ().

Our results indicated that RhoA is rapidly translated in response to synaptic stimulation, and we provided direct evidence that this mechanism represents a critical step for LTP consolidation in the CA1 area of hippocampus. Although this issue remains controversial, dendritic protein synthesis appears to play a critical role in activity-dependent synaptic plasticity in the Schaffer-collateral pathway (; ; ). In addition, several proteins have been shown to be locally synthesized during LTP consolidation (; ; ) or in response to BDNF (). Despite this, there is still limited information regarding the specific proteins whose translation is necessary for LTP consolidation.

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  • Pall ForteBio :: References in Literature

    Targeted transport of messenger RNA and local protein synthesis near the synapse are important for synaptic plasticity

  • 01/03/2007 · Dendritic protein synthesis ..

    15/02/2003 · Local dendritic protein synthesis and synaptic immunity to ..

  • The mouse showed alterations in synaptic plasticity and memory.

    Local protein synthesis in neuronal dendrites is critical for synaptic plasticity

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BDNF + Protein Synthesis = Synaptic Plasticity | Science

RhoA mRNA has been detected in the CA1 neuropil layer as well as in growth cones and synaptoneurosomes (; ; ). The above results suggest that activity-dependent RhoA synthesis takes place in dendrites, where protein synthesis occurs during synaptic plasticity and memory formation (). To test this hypothesis, we compared changes in RhoA protein levels in hippocampal dendritic spines with those of the postsynaptic marker, postsynaptic density 95 (PSD95), by using double immunohistochemistry. Under control conditions, RhoA immunostaining was predominantly found in cell nuclei, as revealed by colocalization with the nuclear dye DAPI, with weak staining in dendritic processes in area CA1 of hippocampus (A,C). Treatment with BDNF for 30 min enhanced RhoA immunofluorescence intensity in CA1 stratum radiatum (A,C,D) as well as its colocalization with PSD95 (F,G). These effects were completely suppressed in slices preincubated with rapamycin (A,C,D). BDNF also increased PSD95 immunofluorescence, but the effect was not blocked by rapamycin (C,E). Notably, somatic RhoA immunostaining was not affected by BDNF (B), indicating that BDNF effects on RhoA levels are restricted to dendrites. To further analyze the effects of BDNF on RhoA subcellular distribution, we quantified RhoA immunostaining in dendritic spines from CA1 using a different RhoA antibody; as opposed to the one used previously (sc-179, polyclonal), this monoclonal antibody (sc-418) did not stain nuclei or dendritic shaft. Instead, it exhibited a punctate pattern with staining in dendritic spines, as evidenced by its partial colocalization with PSD95 (H), a result in good agreement with a previous study using the same antibody in which RhoA staining was found in dendritic spines (where it colocalized with F-actin) but not in the nucleus of cultured neurons (). BDNF treatment significantly increased both the size and the number of puncta-positive for RhoA, compared with control (I,J). Similar results were obtained in the CA3 area of hippocampus. In contrast, BDNF did not enhance dendritic RhoA immunostaining in the dentate gyrus (I,J). Overall, these results confirm that RhoA is rapidly translated in hippocampal dendritic spines in response to BDNF.

for synaptic plasticity and learning/memory

To further confirm that RhoA was newly synthesized in response to BDNF we performed metabolic labeling in cortical synaptoneurosomes using a modified amino acid AHA, which is incorporated into newly translated proteins. We have previously shown that this technique sensitively detected nascent proteins (). Consistent with previous findings using autoradiography (; ), treatment of synaptoneurosomes with BDNF for 30 min significantly increased the levels of de novo synthesized RhoA compared with control. This effect was also blocked by rapamycin and cycloheximide (E,F).

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