Abstract
Neurological diseases associated with neuronal death are also accompanied by axonal denervation of connected brain regions. In these areas, denervation leads to a decrease in afferent drive, which may in turn trigger active central nervous system (CNS) circuitry rearrangement. This rewiring process is important therapeutically, since it can partially recover functions and can be further enhanced using modern rehabilitation strategies. Nevertheless, the cellular mechanisms of brain rewiring are not fully understood. We recently reported a mechanism by which neurons remodel their local connectivity under conditions of network-perturbance: hippocampal pyramidal cells can extend spine head protrusions (SHPs), which reach out toward neighboring terminals and form new synapses. Since this form of activity-dependent rewiring is observed only on some spines, we investigated the required conditions. We speculated, that the actin-associated protein synaptopodin, which is involved in several synaptic plasticity mechanisms, could play a role in the formation and/or stabilization of SHPs. Using hippocampal slice cultures, we found that ~70 % of spines with protrusions in CA1 pyramidal neurons contained synaptopodin. Analysis of synaptopodin-deficient neurons revealed that synaptopodin is required for the stability but not the formation of SHPs. The effects of synaptopodin could be linked to its role in Ca2+ homeostasis, since spines with protrusions often contained ryanodine receptors and synaptopodin. Furthermore, disrupting Ca2+ signaling shortened protrusion lifetime. By transgenically reintroducing synaptopodin on a synaptopodin-deficient background, SHP stability could be rescued. Overall, we show that synaptopodin increases the stability of SHPs, and could potentially modulate the rewiring of microcircuitries by making synaptic reorganization more efficient.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0311-x) contains supplementary material, which is available to authorized users.
Highlights
Functional and structural deficits associated with neurological diseases can be consequences of disruptions in the neuronal microcircuitry [1, 2]
We found that control slices, i.e., slices that were not treated with TTX, had similar numbers of SHPcontaining spines that were synaptopodin-positive or synaptopodin-negative (Fig. 1d)
Not all synaptopodin-positive spines formed a spine head protrusions (SHPs) (Fig. 1d), suggesting that the presence of synaptopodin in a spine is not sufficient to predict the formation of a SHP
Summary
Functional and structural deficits associated with neurological diseases can be consequences of disruptions in the neuronal microcircuitry [1, 2]. We have investigated the role of spines in the rewiring of microcircuits in previous studies and have reported that a subset of innervated spines is able to form spine head protrusions (SHPs), which can form new synapses with neighboring but not yet connected boutons [24, 25]. This phenomenon became much more frequent after exposure of the neurons to the action potential blocker tetrodotoxin (TTX), demonstrating that perturbations in network activity can enhance this mechanism of microcircuit reorganization. Once formed, SHPs grow towards active glutamate sources, suggesting that they are part of a mechanism that allows modifications of an established microcircuit in an activitydependent manner [24, 25]
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