Are synaptic strengths set by co-activity?

Although there is good evidence that Hebbian (co-activity-dependent) synapses do exist, and in some cases the machinery is understood (NMDARs, back-APs etc), and there is also evidence that strength changes underlie learning, only very recently has evidence been obtained that synaptic strength is set by the history of co-activity at that synapse (http://biorxiv.org/content/biorxiv/early/2015/03/11/016329.full.pdf)

The authors used detailed 3D reconstruction from serial EM, and studied pairs of synapses in the hippocampus that were either made by an axon on the same dendrite or on either different dendrites or by different axons (where it's unlikely the axons or dendrites belonged to the same neuron). The idea is that in the former case the 2 synapses would have identical histories of co-activity, and in the latter case, different histories. The above figure shows (A) one example, in which an axon makes 2 synapses on a dendrite (arrows point to the 2 post-synaptic densities, in red) (B) many pairs of examples (C) the relation between the 2 spine head volumes (top) or  PSD areas (next) for the pairs. Spine head volumes or PSD areas should be good measures of synapses strength, and they are tightly correlated for the 2 members of each pair, though they vary over a large range. This suggests that co-activity history determines synapse strength. When the 2 synapses are made by different axons or on different dendrites, the strengths do not correlate well:

A related 3D reconstruction study in the neocortex shows that if an axon makes one synapse on a dendrite, it tends to make others (again consistent with shared co-activity history), though in this case these synapses do not seem to have similar size.

The authors (Kasthuri et al., 2015, Cell 162, 648–661) conclude: " Thus axon-dendrite adjacency, while of course necessary for synapses to form, is insufficient to explain why some axons establish multiple synapses on

some dendrites and not others. This is an explicit refutation of

Peters’ rule. Rather this result argues that there are different

probabilities for synapses between particular dendrites and

particular excitatory axons." Of course a shared history of co-activity and Hebbian plasticity could account for these probabilities.
"Peters' Rule refers to the hypothesis that synapses are made solely on the basis of physical axon and dendrite proximity, without regard to their past history of co-activity. Connections in the brain would then be determined solely by the chance close encounters of axons and dendrites. These in turn would reflect the general geometry of axodendritic overlap, which might reflect genetic specification of axonal arborization dendritic branching patterns. Several recent papers show that this idea is not generally valid, but do not directly suggest a role for co-activity and Hebbian learning. However, there may be situations in which connections do follow Peters' rule. One example would be the bipolar-starburst amacrine synapses I discussed in a recent post.

I favor the extreme opposite view - that connection probabilities and strengths are determined by co-activity and thus indirectly by input correlations - especially by subtle higher-order correlations. This would probably require extraordinary degrees of synapse isolation and independence, and could endow neurons with powerful computational abilities, perhaps transcending what is achievable with current silicon technology. However strong experimental evidence on this point is currently lacking.