Microtubules to form memory
Microtunbule-depolymerizing agents cause amnesia. Some signal translocations to the stimulated postsynaptic membrane are essential for inducing LTP in CA1 neurons like AMPA receptors, CaMKII and mRNA. On the other hand, LTP requires protein synthesis and gene expression. This indicates that signals generated at the synapse might be transmitted to the nucleus. Recently, we have reported that LTP-producing stimulation makes new microtubule track between cell body and the stimulated postsynaptic membrane in CA1 neurons. This newly produced microtubule track only to the stimulated postsynaptic membrane might be the route of these bi-directional transportation of signals during LTP formation. This lead us the hypothesis of the "endless memory amplifying circuit" that means gene expression-promoting molecules are translocated from postsynaptic membrane to the cell body and enter into nucleus and activate transcription factors, and gene products, which will probably promote plasticity, may be re-translocated only to the stimulated postsynaptic membrane along microtubules.
Available from: Shizuko Nagao
- "The newly produced microtubules are localized only to the stimulated postsynaptic spine and that might be the route of the bidirectional dendritic transportation of signals during LTP formation. This led us to hypothesize the " endless memory amplifying circuit " (Figure 3), proposing that retrograde gene expression-promoting molecules, such as CaMKIV, are translocated from postsynaptic membrane to the cell body, enter into the nucleus, and activate transcription factors; anterograde gene products such as AMPA receptors  and CaMKII may be retranslocated only to the stimulated postsynaptic membrane along microtubules, as we have proposed previously  "
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ABSTRACT: There are many microtubules in axons and dendritic shafts, but it has been thought that there were fewer microtubules in spines. Recently, there have been four reports that observed the intraspinal microtubules. Because microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. In contrast, several pieces of evidence suggest that spine elongation may be caused by the polymerization of intraspinal microtubules. This structural mechanism for spine elongation suggests, conversely, that the synapse loss or spine loss observed in Alzheimer's disease may be caused by the depolymerization of intraspinal microtubules. Based on this evidence, it is suggested that the impairment of intraspinal microtubules may cause spinal structural change and block the translocation of plasticity-related molecules between the stimulated postsynaptic membranes and the nucleus, resulting in the cognitive deficits of Alzheimer's disease.
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ABSTRACT: A loss or shortening of dendritic spines has been described in patients with neurodegenerative disorders such as Alzheimer's disease, but the underlying mechanisms are poorly understood. Recently, there have been four reports of capture of the plus-ends of microtubules in the dendritic spines. One report, based on acute hippocampal slices that were fixed by a microtubule preserving process after LTP-inducing stimulation, showed that microtubules of the dendritic shaft ramified into spines in a manner that was specific to the stimulated postsynaptic membranes. This resulted in enlarged protrusion of the dendritic spines. Other reports using living cultured neurons, showed that growing microtubule plus-ends enter spines and modulate spine morphology. Since microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. Several pieces of evidence suggest that spine elongation may be caused by microtubule polymerization. Firstly, the entry of plus-ends of microtubules into spines accompanies spine enlargement. Further, microtubule-associated protein-1B is over-expressed in Fragile X syndrome, in which spines are much elongated. Chronic stress causes neurite outgrowth and spine elongation. Polymerization of microtubules caused neurite outgrowth and microtubules-depolymerizing agents neurite retraction, both consistent with the proposition that spine elongation is caused by microtubule polymerization. This structural mechanism for spine elongation suggests, conversely, that synapse loss or spine shortening observed in Alzheimer's disease may be caused by depolymerization of intraspinal microtubules. The fact that a new drug, dimebon, shows promising results against memory disturbance in Alzheimer's patients and can also cause neurite outgrowth in cultured neurons may also support this idea. Amyloid activates GSK-3beta and it causes the abnormal hyperphosphorylation of tau and depolymerization of axonal microtubules, resulting in the impairment of axonal transport. Normal tau is mainly present in the axon, but hyperphosphorylated tau newly distributes to the dendrites and sequesters normal tau, MAP1A/MAP1B and MAP2, and may cause disruption of intraspinal microtubules by losing the microtubule-preserving effect of MAPs. Nevertheless, it may be strongly suspected that amyloid beta may be a putative intra-spinal microtubule-depolymerizer to induce spine shortening, synaptic loss and finally the memory disturbance in Alzheimer's disease.
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ABSTRACT: The goal of this essay is to link the regulation of actin dynamics to the idea that the synaptic changes that support long-term potentiation and memory evolve in temporally overlapping stages-generation, stabilization, and consolidation. Different cellular/molecular processes operate at each stage to change the spine cytoarchitecture and, in doing so, alter its function. Calcium-dependent processes that degrade the actin cytoskeleton network promote a rapid insertion of AMPA receptors into the post synaptic density, which increases a spine's capacity to express a potentiated response to glutamate. Other post-translation events then begin to stabilize and expand the actin cytoskeleton by increasing the filament actin content of the spine and reorganizing it to be resistant to depolymerizing events. Disrupting actin polymerization during this stabilization period is a terminal event-the actin cytoskeleton shrinks and potentiated synapses de-potentiate and memories are lost. Late-arriving, new proteins may consolidate changes in the actin cytoskeleton. However, to do so requires a stabilized actin cytoskeleton. The now enlarged spine has properties that enable it to capture other newly transcribed mRNAs or their protein products and thus enable the synaptic changes that support LTP and memory to be consolidated and maintained.
Copyright © 2014. Published by Elsevier B.V.
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