Elsevier

Current Opinion in Neurobiology

Volume 63, August 2020, Pages 189-197
Current Opinion in Neurobiology

Structural LTP: from synaptogenesis to regulated synapse enlargement and clustering

https://doi.org/10.1016/j.conb.2020.04.009Get rights and content

Highlights

  • Structural LTP produces opposite effects at synapses on immature versus adult dendrites.

  • Local subcellular compartments mediate synaptogenesis at P15 and synapse enlargement in adults.

  • A unified theory of resource-dependent silent spinogenesis and synapse enlargement is presented.

Nature teaches us that form precedes function, yet structure and function are intertwined. Such is the case with synapse structure, function, and plasticity underlying learning, especially in the hippocampus, a crucial brain region for memory formation. As the hippocampus matures, enduring changes in synapse structure produced by long-term potentiation (LTP) shift from synaptogenesis to synapse enlargement that is homeostatically balanced by stalled spine outgrowth and local spine clustering. Production of LTP leads to silent spine outgrowth at P15, and silent synapse enlargement in adult hippocampus at 2 hours, but not at 5 or 30 min following induction. Here we consider structural LTP in the context of developmental stage and variation in the availability of local resources of endosomes, smooth endoplasmic reticulum and polyribosomes. The emerging evidence supports a need for more nuanced analysis of synaptic plasticity in the context of subcellular resource availability and developmental stage.

Introduction

Analysis of LTP provides a powerful window into cellular mechanisms of learning. Hence, LTP is mostly studied in the hippocampus, a brain region required to form memories. The importance of prior activation history and specific induction paradigms are increasingly emphasized to understand mechanisms of LTP [1, 2, 3]. Dendritic spines are tiny protrusions that stud the surface of dendrites and host most of the excitatory synapses throughout the brain. The importance of context arises even when single spine synapses are potentiated by glutamate uncaging [3]. Most experiments image changes in spine structure as a proxy for synapse growth, and usually end within an hour after onset of potentiation. Such experiments have revealed exquisite detail about molecular and cellular mechanisms controlling spine structural plasticity during the early phase of LTP. Here we consider more enduring structural LTP in the context of developmental stage and availability of local resources.

Section snippets

LTP enhances synaptogenesis at P15 but stalls spine outgrowth in adults

To investigate enduring LTP, hippocampal slices are prepared, allowed to rest for 3−4 hours, and then test pulses are delivered at a frequency of one per 2 min for 30−40 min to establish baseline response. Then LTP is induced with a pattern of theta-burst stimulation (TBS) that fully saturates LTP [4,5]. The number and frequency of test pulses is matched in control and LTP conditions for varying times post-TBS. Three-dimensional reconstruction from serial section electron microscopy (3DEM)

Resource dependent synapse enlargement and synaptogenesis

Multiple subcellular resources contribute locally to structural LTP. Smooth endoplasmic reticulum (SER) is a continuous internal membrane system that extends from the cell body into dendrites and into some spines. The SER regulates calcium and the synthesis and trafficking of lipids and proteins [8]. In locations where the SER elaborates, ER exit sites abound and can deliver resources of membrane and proteins to synapses [9••]. The spine apparatus is a structure elaborated from SER into

Maturation of homeostasis and spine clustering

Recent experiments using optogenetics, live imaging, and computational models suggest that clusters of spines cooperate to enhance the efficacy of particular inputs during plasticity and learning [18,19••,20,21,22, 23, 24]. The redistribution of subcellular resources could be critical in determining where such spine clustering hotspots arise. During LTP, do the enlarging synapses on SA-containing spines sequester resources and prevent neighboring spine outgrowth, or do they share with

Silent formation and enlargement of synapses

Curiously, synaptogenesis and synapse enlargement appear to be silent at P15 and adult hippocampus. Enhanced synaptogenesis with LTP (P15) or recovery of spines during control stimulation in adults are both silent. This conclusion is obvious from looking at the time course of spine formation during control stimulation or LTP relative to the physiological response across time during LTP experiments (Figure 4a). In adults, if the spines that recovered in response to control stimulation were

Presynaptic axons track postsynaptic changes

Presynaptic plasticity is also developmentally regulated by LTP [28, 29, 30]. At P15, more presynaptic boutons form to accommodate the LTP-induced synaptogenesis. In adults, fewer presynaptic boutons accompany stalled spine outgrowth after LTP. At both ages, a drop in presynaptic vesicles remains for at least 2 hours after TBS-induction of LTP, especially in boutons with mitochondria [29]. This drop could reflect the elevated recycling of presynaptic vesicles detected 30 min post induction of LTP

Other considerations

Several other factors may contribute to the maturation of homeostasis and dendritic spine clustering. We focused here on the extent to which dendritic shaft SER and the associated ER exit sites may serve to define regions of dendritic spine clustering. The post-LTP spread of numerous other molecules may be restricted to individual spines or short regions of the dendritic shaft [2,33,34]. Differential expression of calcium-permeable AMPA receptors could influence the range over which a calcium

Conclusion

Despite dramatic structural plasticity, and daily turnover of synaptic proteins, memories stored in synapses show remarkable tenacity. Synapse stabilization appears to require reactivation, especially during sleep [41,42]. Failure of synapses to form, grow, or remodel is likely responsible for many developmental and age-related disorders. [43]. It remains unclear whether dendritic spine loss is a cause or consequence. Observing that dendrites retain immature varicosities and filopodia in

Conflict of interest statement

Nothing declared.

Funding

R01MH095980 NSF NeuroNex Neurotechnology Hub #1707356.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as

  • • of special interest

  • •• of outstanding interest

Acknowledgement

I thank Patrick Parker for editorial comments and Masa Kuwajima for help with Figure 3.

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