Predictive control of structural plasticity

Determine whether synaptic rewiring is governed primarily by identifiable molecular, cellular, activity-dependent, and resource-related predictors or whether it contains an irreducible component of biological randomness, thereby establishing how neuronal networks control the formation, stabilization, and elimination of synapses.

Background

The paper reviews evidence that neuronal activity, synaptic weight, spine morphology, age, local dendritic neighborhoods, organelles, cell adhesion molecules, glia, and extracellular matrix components all influence synapse turnover. Nevertheless, these factors do not yet permit precise prediction of where and when synapses will form, stabilize, or disappear.

The unresolved issue is whether the apparent stochasticity of structural plasticity reflects incomplete knowledge of relevant predictors, genuine biological randomness, or a combination of both. Resolving this issue would require integrating longitudinal connectomics, molecular measurements, and multiscale computational models.

References

Moreover, there is still a lot of uncertainty in predicting where synapses will be formed, stabilized or eliminated, and there is turnover even when activity is blocked. Thus, the perceived randomness of synaptic rewiring may stem from a combination of limited predictability due to an incomplete set of predictors as well as actual biological randomness implying that structural plasticity may only partly be controlled by the neuronal network.

— Rewiring of adult neural networks - learning from structural plasticity across multiple scales  (2610.18024 - Fauth et al., 13 Oct 2026) in Section 1, subsection “Open problems,” paragraph “How is structural plasticity controlled?”

As network function also strongly depends on inhibitory connections~\citep{Mongillo2018}, it is clear that we also need to know how the above factors co-modulate inhibitory and excitatory structural plasticity and whether there are more factors to take into account.

— Rewiring of adult neural networks - learning from structural plasticity across multiple scales  (2610.18024 - Fauth et al., 13 Oct 2026) in Section 1, subsection “Open problems,” paragraph “Synapse-type-dependent mechanisms”

As discussed in Section~\ref{sec:regulation}, the emergence of synapse clustering on dendrites \citep{Fu2012,Chen2012} poses the fundamental question whether it is driven by the local activity in the dendrite or by molecular cues, or even by a combination of both.

— Rewiring of adult neural networks - learning from structural plasticity across multiple scales  (2610.18024 - Fauth et al., 13 Oct 2026) in Section 2, subsection “Open problems,” paragraph “The emergence and impact of dendritic clustering”