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bioRxiv · 10.1101/2025.11.24.690115

Intrinsic excitability controls structural plasticity of cerebellar climbing fibers

Musto, M.·Bergamini, M.·La Terra, A.·Marte, A.·Marenco, G.·Lo Iacono, F.·Benfenati, F.·Grasselli, G.
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Abstract

In the cerebellum, climbing fibers (CFs) convey a teaching signal to Purkinje cells (PCs) that is crucial for cerebellar learning. They undergo activity-dependent synaptic plasticity during development and learning, and their transverse branches have an activity-dependent control of mobility. The maintenance of their structure was shown to rely on the growth-associated protein 43 (GAP-43), which is highly expressed in these fibers under basal conditions in adults and which is controlled by intracellular calcium levels and phosphorylation. Although activity-dependent structural plasticity occurs in several axonal fibers throughout the brain, it remains unclear whether this is also the case for the main branches of CFs. Here, we investigate this issue using in vivo knock-down of voltage-gated sodium channels (NaVs) in the CF-generating neurons of the inferior olive, and analyzing CF three-dimensional morphology, density and function of synaptic contacts with PCs. We show that the decrease in intrinsic excitability causes a reduction in the number and length of CF branches and that similar effects are caused by the knockdown of GAP-43, suggesting that GAP-43 may mediate this response. We also show that the retraction of CF fibers is associated with a seemingly compensatory increase in the density of CF synaptic terminals and PC dendritic spines, specifically in the area where PCs receive CF inputs. These plastic modifications are associated with a decrease in paired-pulse ratio and an increase in the kinetics and transferred charge of synaptic currents. Our data show that CFs can undergo activity-dependent structural plasticity changes affecting synaptic transmission and suggest the possibility that they contribute to encoding memories in the cerebellum and, if disrupted, to the pathophysiology of cerebellar diseases.

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Musto, M., Bergamini, M., La Terra, A., Marte, A., Marenco, G., Lo Iacono, F., Benfenati, F., Grasselli, G.. 2025-11-25. Intrinsic excitability controls structural plasticity of cerebellar climbing fibers. https://doi.org/10.1101/2025.11.24.690115

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