Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules

Abstract

Memory storage involves activity-dependent strengthening of synaptic transmission, a process termed long-term potentiation (LTP). The late phase of LTP is thought to encode long-term memory and involves structural processes that enlarge the synapse. Hence, understanding how synapse size is graded provides fundamental information about the information storage capability of synapses. Recent work using electron microscopy (EM) to quantify synapse dimensions has suggested that synapses may structurally encode as many as 26 functionally distinct states, which correspond to a series of proportionally spaced synapse sizes. Other recent evidence using superresolution microscopy has revealed that synapses are composed of stereotyped nanoclusters of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and scaffolding proteins; furthermore, synapse size varies linearly with the number of nanoclusters. Here we have sought to develop a model of synapse structure and growth that is consistent with both the EM and super-resolution data. We argue that synapses are composed of modules consisting of matrix material and potentially one nanocluster. LTP induction can add a trans-synaptic nanocluster to a module, thereby converting a silent module to an AMPA functional module. LTP can also add modules by a linear process, thereby producing an approximately 10-fold gradation in synapse size and strength.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.

Synaptic nanomodules underlie the organization and plasticity of spine synapses

“…Activity-dependent structural plasticity of individual spines results in long-lasting increases in the number of modules. These findings are reminiscent of previous work in the hippocampus suggesting an all-or-none model of synaptic plasticity 38 , recent modeling work 39 , and are consistent with the observation that some dendritic spines may contain perforated PSDs 22 , 40 , 41 . The nano-organization of pre- and post-synaptic proteins was remarkably similar in vitro and in brain slices from cortex suggesting that these are robust features of the synapse.…”

Nanostructural Diversity of Synapses in the Mammalian Spinal Cord

“…Our structural analyses reveal that VGLUT1 boutons were larger than VGLUT2 boutons, and often contacted multiple distinct PSDs, indicative of Type II glomeruli that are widely reported in the dorsal horn laminae III-IV and associated with both VGLUT1 and VGLUT3 expression 29,81,82 . Additionally, we now show that the PSDs associated with VGLUT1 are typically larger and contain a greater number of PSD95 NCs than those associated with VGLUT2, which would tentatively suggest that VGLUT1 synapses form stronger connections 72,73 . From studies of cell cultures and other CNS regions, VGLUT1 synapses exhibit a lower initial probability of release, are associated with larger amplitude postsynaptic potentials and show synaptic facilitation, while VGLUT2 synapses exhibit a higher probability of release, transmit signals with a greater fidelity and show synaptic depression [83][84][85][86][87] .…”

“…This nanoarchitecture is thought to enable action-potential-evoked vesicular release at directly opposing postsynaptic receptor domains for increased synaptic efficiency 1 . It is believed that the size of the synapse, as determined by the number of NCs and associated presynaptic release sites, is correlated with the strength of the synapse 72 . From the findings of others 4,5,18,19,73 , and the super-resolution analysis presented here, a set of rules begin to emerge regarding the nanostructural organisation of the PSD: 1) PSDs vary in the number of NCs they contain; 2) the size and morphology of NCs is relatively conserved across different regions, ages, and irrespective of any association with astrocytes; 3) the concentration of PSD95 molecules within NCs can vary.…”

The Synaptic Theory of Memory: A Historical Survey and Reconciliation of Recent Opposition

“…Subsequent activity in “A” encoding neurons can then, through spreading activation, elicit activity in the neurons encoding “B” thus providing a neural link between the cell assemblies (a phase sequence) representing each of these two originally discrete stimuli (Anderson, 1983 ). As discussed in “Evidence From Spatial Training Suggests That There Is a Need to Separate Learning From Memory” section, learning and memory occur along a continuum, so the fact that synaptic encoding of a memory requires “a great many molecules to realize” is a benefit as it allows for the gradation of synaptic, and in turn memory, strength along a continuum in accordance with the salience of the information, or effortfulness of original learning (Liu et al, 2017 ). Furthermore, the biochemical and structural complexity of the glutamatergic synapse, actualized by these “great many molecules,” allows for several distinct forms of plasticity: (i) STP; (ii) early or late LTP (E-LTP or L-LTP); (iii) LTD; (iv) synaptic scaling; and (v) distance-dependent scaling (Volianskis et al, 2013 ; Lisman, 2017a ).…”