Calcium changes following backpropagation of spikes would allow synapses to estimate their distance from the soma

Due to randomness in neurodevelopment, it is an unavoidable constraint on neural morphology that some synapses will be further away from the soma than others.

And due to the vagaries of membrane electrophysiology, membrane potential changes will degrade continuously on their journey to the soma.

So, in the absence of an adjustment mechanism, the potentials of more distant synapses would be more degraded when they reach the soma and have a proportionally smaller impact on whether the neuron should spike.

For certain cell types, evolution would probably like to eliminate this bias (“no ion channel taxation without representation”). But the mechanism by which they might do so is unclear.

A modeling study provides intriguing evidence that hippocampal pyramidal neurons adjust for this via homeostatic scaling of the maximum calcium concentration at synapses following action potential backpropagation.

As you can see below, the authors found a strongly negative correlation between the distance from a spine to the soma and its maximum calcium concentration.

Because distance from the soma and EPSP degradation are correlated, they also found a strongly negative association between the degree to which excitatory potentials attenuate on their journey to the soma and their max calcium concentration.

left = model pyramidal neuron with spines; colored circles = locations of spines demarcated in the scatter plots; path distance = 3d separation from the soma to that spine

The main problem with the model is that if synapses really are in a true “synaptic democracy”, then homeostatic scaling to this feature wouldn’t be strong enough to be the only reason why. Figure 8F simply does not show a distribution of jointly independent variables.

Plus, figure 1H shows that almost all of the variance in peak calcium concentration is for synapses <400 microns from the soma. How would you achieve equality of representation between synapses 400 um and 800 um away?

Still, this is a nice example of a structure-function relationship at the synapse level and is a hypothesis wholly worth testing.

Reference

Sterratt DC, Groen MR, Meredith RM, van Ooyen A (2012) Spine Calcium Transients Induced by Synaptically-Evoked Action Potentials Can Predict Synapse Location and Establish Synaptic Democracy. PLoS Comput Biol 8(6): e1002545. doi:10.1371/journal.pcbi.1002545

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Proteins differentially expressed in the aging hippocampus

In their review of the “neuroproteome” associated with aging and cognitive decline, VanGuilder and Freeman discuss some of the technical approaches and findings in the field.

This illustrative figure shows some of the major cellular players involved and lists some example proteins involved in four important pathways:

"numerous cell types (microglia (green), astrocytes (orange), oligodendrocytes (blue), and neurons (violet)) and subcellular components (mitochondria (brown), endoplasmic reticulum (green), cytoskeleton (orange/red), and synaptic machinery) are affected by brain aging"; doi: 10.3389/fnagi.2011.00008

As you can see, many proteins have been implicated, although the degree of up-/down-regulation of these proteins is not fully elucidated.

The authors mention the value of standardizing efforts to profile the proteome in important brain regions across the lifespan of rodent models. This step would make these results more robustly quantitative and help iterate towards a consensus.

Reference

VanGuilder H. D. and Freeman W. M (2011) The hippocampal neuroproteome with aging and cognitive decline: past progress and future directions. Front. Ag. Neurosci. 3:8. doi: 10.3389/fnagi.2011.00008