Synaptic Structural Remodeling Research Articles

Removing synaptic brakes on learning.

Imaging experiments in awake mice reveal striking, circuit-specific synaptic structural remodeling of inhibitory axons during learning.

Presynaptic protein synaptotagmin1 regulates the activity‐induced remodeling of synaptic structures in cultured hippocampal neurons

Activity-dependent reorganizations of central neuronal synapses are thought to play important roles in learning and memory. Although the precise mechanisms of how neuronal activities modify synaptic connections in neurons remain to be clarified, the activity-induced neuronal presynaptic proteins such as synaptotagmin1 may contribute to the onset of synaptic remodeling. To understand better the physiological roles of synaptotagmin1, we first examined the prolonged effects of neuronal stimulation capable of inducing synaptotagmin1 on the distribution of a postsynaptic proteins (PSD) protein Homer1c by immunostaining. Previously we found that glutamate stimulation induced other postsynaptic proteins, such as postsynaptic density-95 (PSD95), a biphasic change with an initially diffuse distribution after 30 min to 1 hr, followed by reassembly to more than the original level after 4-8 hr, suggesting that glutamate stimulation induces a global biphasic alteration in synaptic structures. To dissect further the functions of synaptotagmin1 in the activity-induced synaptic remodeling, short hairpin RNA (shRNA) vectors that specifically block the expression of endogenous synaptotagmin1 were constructed. When the shRNA of synaptotagmin1 was introduced to the neurons, the activity-induced changes were almost completely suppressed. We found that synaptotagmin1 contributes to the postsynaptic remodeling in a retrograde manner. Our data indicate that synaptotagmin1 regulates the activity-induced biphasic changes of post- and presynaptic sites.

Abstract WP92: Human Neural Stem Cells Enhance Synaptic Structural Remodeling in the Ischemic Brain.

Introduction: Stem cell transplantation has emerged as a promising new experimental treatment for stroke; understanding its mechanism of action will facilitate the translation of stem cell therapy to the clinic. Previous work from our lab and others suggests that transplanted stem cells function by enhancing endogenous brain repair processes including structural brain plasticity. The ultimate change in brain plasticity is manifested at the synaptic level and thus we hypothesize that stem cells will enhance synaptic structural remodeling in the post-ischemic brain. To test this we use array tomography, a new high-resolution proteomic imaging method, to determine a) the number and subtype of glutamate and GABA synapses after stroke, and b) how these parameters are affected by transplantation of human neural progenitor cells (hNPCs). Method: Vehicle or hNPCs derived from fetal cortex were transplanted into the ischemic cortex of Nude rats at 7 days after distal middle cerebral artery occlusion. Neurological recovery was assessed weekly using a battery of behavioral tests. Small tissue was removed from the peri-infarct cortex at 4 weeks post-transplantation. The tissue was processed and ribbons, or arrays, of serial ultrathin sections (70 nm) were obtained using an ultramicrotome. Ribbons were stained with antibodies for the synaptic markers Synapsin1, VGlut1, VGlut2, PSD-95, GAD, VGAT, GABAAR-α1, and images taken in cortical layer 2/3 and layer 5. Computational analysis of the resultant staining pattern was used to identify and quantify subtypes of glutamatergic and GABAergic synapses. Results: Transplantation of hNPCs significantly improved behavioral recovery after stroke compared to vehicle-treated rats (4 weeks; p<0.01, n=9). There was an increase in the density and proportion of glutamatergic synapses expressing VGluT2 in layer5 at 4 weeks post-transplantation (Density: 0.090 vs 0.057 synapses/μm3. Proportion: 27.0 vs 22.6 %, n=4). No detectable differences in the density of GABAergic synapses were observed. Conclusions: These results suggest that stem cells alter synaptic remodeling after stroke and this is coincident with stem cell-induced functional recovery.

Synaptic loss and retention of different classic cadherins with LTP‐associated synaptic structural remodeling in vivo

Cadherins are synaptic cell adhesion molecules that contribute to persistently enhanced synaptic strength characteristic of long-term potentiation (LTP). What is relatively unexplored is how synaptic activity of the kind that induces LTP-associated remodeling of synapse structure affects localization of cadherins, particularly in mature animals in vivo, details which could offer insight into how different cadherins contribute to synaptic plasticity. Here, we use a well-described in vivo LTP induction protocol that produces robust synaptic morphological remodeling in dentate gyrus of adult rats in combination with confocal and immunogold electron microscopy to localize cadherin-8 and N-cadherin at remodeled synapses. We find that the density and size of cadherin-8 puncta are significantly diminished in the potentiated middle molecular layer (MML) while concurrently, N-cadherin remains tightly clustered at remodeled synapses. These changes are specific to the potentiated MML, and occur without any change in density or size of synaptophysin puncta. Thus, the loss of cadherin-8 probably represents selective removal from synapses rather than overall loss of synaptic junctions. Together, these findings suggest that activity-regulated loss and retention of different synaptic cadherins could contribute to dual demands of both flexibility and stability in synapse structure that may be important for synaptic morphological remodeling that accompanies long-lasting plasticity.

SCG10-related neuronal growth-associated proteins in neural development, plasticity, degeneration, and aging.

Neuronal growth-associated proteins (nGAPs) are in general neuron-specific gene products whose expression correlates tightly with neuronal process outgrowth and/or regeneration, and are mostly good downstream targets of neurotrophin stimulation. Expression of genes encoding nGAPs such as GAP-43, SCG10, and stathmin is upregulated following lesioning of cortical and hippocampal regions of the adult rat brain. In the brains of aged animals, however, the magnitude of the response is reduced, whereas the time course of the response is mostly unchanged when compared with that for brains of young ones. Expression of GAP-43 and stathmin is reduced by aging, and is also changed in age-related neurodegenerative conditions such as Alzheimer's disease in humans. Certain nGAPs are induced during long-term potentiation (LTP) and also during critical periods of song-learning and ocular dominance column formation in birds and cats, respectively. Recent evidence further supports the idea that functional synaptic modulation is often associated with remodeling of synaptic structures. These results suggest that neurotrophin-responsive nGAPs serve as molecular markers of neuronal plasticity during development and aging, and that the neuronal plasticity decreases, at least in certain neuronal circuits, in the aged brain and neurodegenerative diseases. Recent findings on the roles of stathmin and SCG10-related proteins in microtubule destabilization and its functional block by phosphorylation further support the importance of the SCG10 family proteins in neuronal cytoskeletal regulation, particularly as to microtubule dynamics. We summarize here a decade of research on SCG10 and its related molecules with special interests to brain aging and disease.

Rapid structural remodeling of shaft synapses associated with long-term potentiation in the cat superior cervical ganglion in situ.

Synaptic plasticity associated with long-term potentiation was studied electrophysiologically and ultrastructurally in the cat superior cervical ganglion in situ. The preganglionic nerve fiber was stimulated at 10 Hz for 50 s for conditioning and then at 1 Hz for 1-3 h to monitor changes in the postganglionic compound action potential (PGP). The present material has shown the long-term potentiation (LTP), around 120% of the control, which lasted for up to 3 h. Fifteen of 18 ganglia (83%) have shown LTP. Ultrastructural studies demonstrated the synaptic structural remodeling: (1) The preganglionic nerve terminals ordinarily made mainly asymmetrical type of shaft synapses directly with dendrites of the ganglion cells that lacked dendritic spines; (2) conditioning tetanus rapidly remodeled simple shaft synapses into perforated ones characterized by perforations in the postsynaptic density (PSD), some of which had synaptic spinules associated with the perforated PSDs, i.e. spinule-synapses; (3) a rapid increase in the number of both structures was detected immediately after the tetanus. Perforated synapses and the spinule-synapses increased from 5% and 0% in the control to 27 and 9% at 0 min, respectively. Spinule-synapses occurred about one-third of the perforated shaft synapses; (4) Increased numbers of restructured shaft synapses was maintained for 15 min in ganglia expressing LTP; (5) Remodeled synapses did not increase in ganglia that did not express LTP or ganglia that were activated at 0.5 or 1 Hz. It was suggested a rapid increase in the number of remodeled synapses associated with the onset of LTP and its durability at its earlier phases in the cat SCG.

Molecules involved in the formation of synaptic connections in muscle and brain.

Synapses are highly specialized structures designed to guarantee precise and efficient communication between neurons and their target cells. Molecules of the extracellular matrix have an instructive role in the formation of the neuromuscular junction, the best-characterized synapse. In this review, the molecular mechanisms underlying these instructive signals will be discussed with particular emphasis on the receptors involved. Additionally, recent evidence for the involvement of specific adhesion complexes in the formation and modulation of synapses in the central nervous system will be reviewed. Synapses are specialized junctions between neurons and their target cells where information is transferred from the pre- to the postsynaptic cell. At most vertebrate synapses, this transfer is accomplished by the release of a specific neurotransmitter from the presynaptic nerve terminal. The release of neurotransmitter is initiated by the action potential and the subsequent influx of Ca(2+) into the presynaptic nerve terminal. This results in the rapid fusion of vesicles with the nerve membrane and the release of the neurotransmitter into the synaptic cleft. The neurotransmitter then diffuses across the cleft and binds to specific postsynaptic receptors, resulting in a change in the membrane potential of the postsynaptic cell. This can result in the generation of an action potential. The high precision of synaptic transmission requires that pre- and postsynaptic structures are both highly organized and in juxtaposition to each other. In addition, alterations in synaptic transmission are the basis of learning and memory and are likely to be accompanied by the remodeling of synaptic structures (Toni et al., 1999). Thus, the study of how synapses are formed during development is also of relevance for the understanding of the cellular and molecular processes involved in learning and memory. This review focuses on the molecular mechanisms involved in the formation and the function of synapses.