One Unknown
The semblance hypothesis has identified multiple lines of indirect evidence supporting the plausibility of the IPL mechanism (see Evidence page). However, no studies have yet investigated inter-neuronal inter-spine interactions to test for the presence of IPLs. The IPL mechanism consists of inter-dendritic branch inter-spine interactions between spines, mainly belonging to different neurons, and is expected to involve the following spectrum of changes.
1. At the most transient end of the spectrum, a localized electrical field can form between inter-LINKed spines. Given that extracellular potentials can influence nearby neuronal membranes through ephaptic coupling [1, 2], and that abutted spines at IPL-eligible sites are separated by as little as 10–30 nm of extracellular space [3, 4], it is possible to infer that such fields could permit highly reversible, rapid voltage transfer between spine heads without persistent structural change.
2. Experimental data suggest that AMPA receptor-containing vesicles with small diameters fuse with spine membrane due to VAMP2 [5]. This is crucial for AMPA receptor delivery to the postsynaptic membrane, a key process in LTP induction [6] that can be explained in terms of IPL formation [7].
3. A third testable mechanism involves redox-mediated inter-spine bridging. When spines get abutted more closely (e.g., due to spine expansion by released dopamine [8], redox-active amino acids such as C103 of VAMP2 from two abutted spines become exposed to the aqueous extracellular medium. When synaptic activity induces local oxygen depletion [9], this along with the release of metal ions like Zn2+ into the extrasynaptic space [10], can facilitate the formation of metal complexes [11] that bridge the spines and facilitate voltage transfer.
4. Postsynaptic SNARE proteins are essential for activity-dependent membrane remodeling at dendritic spine margins [12], affecting membrane tension, curvature, and lipid organization, and bringing abutted spines closer together. SNARE proteins overcome curvature-induced energy barriers, thereby initiating hemifusion [13]. SNAREs also generate force to tightly appose membranes [14], forming characteristic hemifusion intermediates [15]. SNARE-mediated fusion of AMPA receptor-containing vesicles with the spine membrane [16] potentially contributes membrane material to lateral spine regions. Based on the semblance hypothesis, SNARE proteins play a key role in IPL formation during LTP induction by repurposing fusion machinery to facilitate inter-spine interactions [7]. During heightened synaptic activity, this may allow for transient hemifusion or restricted membrane continuity between abutted postsynaptic membranes, that stops short of full fusion.
References
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