Abstract
In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity1. Reduction in synapse number is a consistent early feature of neurodegenerative diseases2, 3, suggesting deficient compensatory mechanisms. While much is known about toxic processes leading to synaptic dysfunction and loss in these disorders2,3, how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity4, 5. We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number cold-shock proteins in the brain, including the RNA binding protein, RBM36. The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5×FAD (Alzheimer-type) mice7, the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. Further, RBM3 over-expression, achieved either by boosting endogenous levels through hypothermia prior to the loss of the RBM3 response, or by lentiviral delivery, resulted in sustained synaptic protection in 5×FAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold shock pathways as potential protective therapies in neurodegenerative disorders.
Highlights
In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity[1]
We used the phenomenon of physiological structural plasticity seen in hibernating mammals to determine the capacity for synapse regeneration in mouse models of neurodegenerative disease
We first established that the phenomenon of synapse dismantling and reassembly on artificial cooling and rewarming occurs in laboratory mice (Figure 1a and Extended Data Figure 1a)
Summary
In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity[1]. We tested the capacity for structural plasticity using cooling early in the course of disease, before the onset of established synapse loss in both models: from 4 w.p.i. in prion-infected animals and from 2 months of age in 5×FAD mice. Wild type mice showed synaptic structural plasticity with reduction in synapse number on cooling and recovery on rewarming (Figure 1a).
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