Local resources of polyribosomes and SER promote synapse enlargement and spine clustering after long-term potentiation in adult rat hippocampus

Abstract

Synapse clustering facilitates circuit integration, learning, and memory. Long-term potentiation (LTP) of mature neurons produces synapse enlargement balanced by fewer spines, raising the question of how clusters form despite this homeostatic regulation of total synaptic weight. Three-dimensional reconstruction from serial section electron microscopy (3DEM) revealed the shapes and distributions of smooth endoplasmic reticulum (SER) and polyribosomes, subcellular resources important for synapse enlargement and spine outgrowth. Compared to control stimulation, synapses were enlarged two hours after LTP on resource-rich spines containing polyribosomes (4% larger than control) or SER (15% larger). SER in spines shifted from a single tubule to complex spine apparatus after LTP. Negligible synapse enlargement (0.6%) occurred on resource-poor spines lacking SER and polyribosomes. Dendrites were divided into discrete synaptic clusters surrounded by asynaptic segments. Spine density was lowest in clusters having only resource-poor spines, especially following LTP. In contrast, resource-rich spines preserved neighboring resource-poor spines and formed larger clusters with elevated total synaptic weight following LTP. These clusters also had more shaft SER branches, which could sequester cargo locally to support synapse growth and spinogenesis. Thus, resources appear to be redistributed to synaptic clusters with LTP-related synapse enlargement while homeostatic regulation suppressed spine outgrowth in resource-poor synaptic clusters.

The Spatial Scale of Synaptic Protein Allocation during Homeostatic Plasticity

“…Fig. 4B yellow neighborhoods) included synapse clusters similar to what has been previously described (4,7,28,30). We measured the synapse density and synaptic protein density of every neighborhood, in addition to other characteristics such as neighborhood size, synapse number, and synaptic-protein per-synapse ( Fig.…”

“…Biological compartments can function and adapt with autonomy by localizing cell biological organelles and machinery. Perhaps the best example of this is the neuronal synapse, where local control of protein production and degradation allows for the compartmentalization of synaptic function and plasticity (1)(2)(3)(4). This creates a logistical challenge for the neuron: it must allocate its proteins between thousands of synapses to maintain their parallel computing while still 5 fulfilling individual plasticity demands.…”

“…This creates a logistical challenge for the neuron: it must allocate its proteins between thousands of synapses to maintain their parallel computing while still 5 fulfilling individual plasticity demands. It remains unknown how a neuron accomplishes this large-scale resource allocation to balance local autonomy (3)(4)(5) with global homeostasis (6).…”

“…using PSD-95 immuno-labeling as a proxy) and the current or future functional efficacy of the synapse (26,27). (3,4,28). This suggests that the relevant spatial scale for synaptic 20 protein allocation might comprise neighborhoods of synapses within dendrites ( Fig.…”

Developmental onset of enduring long-term potentiation in mouse hippocampus

“…The delay between episodes of TBS reflects the time needed to enlarge the synapses after the initial induction of LTP in adult rats (Bell et al, 2014). In adults, this synaptic enlargement is also homeostatically balanced by stalled spine outgrowth which reflects the temporal dynamics of resource reallocation at different times after the induction of LTP (Bell et al, 2014;Chirillo et al, 2019). Others have shown in adult rats that TBS-induced L-LTP and unsupervised learning enhance actin polymerization and growth via phosphorylation of cofilin, especially in large spines (Chen et al, 2007;Fedulov et al, 2007).…”