Abstract
In chronic neurodegenerative diseases associated with aggregates of misfolded proteins (such as Alzheimer's, Parkinson's and prion disease), there is an early degeneration of presynaptic terminals prior to the loss of the neuronal somata. Identifying the mechanisms that govern synapse degeneration is of paramount importance, as cognitive decline is strongly correlated with loss of presynaptic terminals in these disorders. However, very little is known about the processes that link the presence of a misfolded protein to the degeneration of synapses. It has been suggested that the process follows a simple linear sequence in which terminals that become dysfunctional are targeted for death, but there is also evidence that high levels of activity can speed up degeneration. To dissect the role of activity in synapse degeneration, we infused the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of mice with prion disease and assessed synapse loss at the electron microscopy level. We found that injection of BoNT/A in naïve mice caused a significant enlargement of excitatory presynaptic terminals in the hippocampus, indicating transmission impairment. Long-lasting blockade of activity by BoNT/A caused only minimal synaptic pathology and no significant activation of microglia. In mice with prion disease infused with BoNT/A, rates of synaptic degeneration were indistinguishable from those observed in control diseased mice. We conclude that silencing synaptic activity neither prevents nor enhances the degree of synapse degeneration in prion disease. These results challenge the idea that dysfunction of synaptic terminals dictates their elimination during prion-induced neurodegeneration.
Highlights
Since the first suggestion that synaptic loss is associated with the degree of cognitive decline in Alzheimer’s disease (AD) [1] there has been a growing body of evidence to show that synapse loss is an early component of the neuropathology of chronic neurodegenerative diseases associated with the accumulation of misfolded proteins such as AD, Parkinson’s disease, Huntington’s disease and prion disease
In order to understand whether synaptic activity is an important determinant of synapse degeneration we have investigated whether prolonged blockade of synaptic activity impacts on synapse degeneration in prion disease
Following direct injection into the brain parenchyma have not been previously studied, there have been reports on the impact of botulinum neurotoxin A (BoNT/A) and tetanus neurotoxin on neurons of the peripheral nervous system [28,29]. We addressed this issue by injecting adult mice into the left hippocampus with BoNT/A (1 nM solution, 0.2 ml; n = 13 animals) or vehicle solution (0.2 ml of 2% rat serum albumin in PBS; n = 13)
Summary
Since the first suggestion that synaptic loss is associated with the degree of cognitive decline in Alzheimer’s disease (AD) [1] there has been a growing body of evidence to show that synapse loss is an early component of the neuropathology of chronic neurodegenerative diseases associated with the accumulation of misfolded proteins such as AD, Parkinson’s disease, Huntington’s disease and prion disease. In laboratory models of prion disease there is well documented degeneration of synapses from the hippocampus prior to the degeneration of neuronal cell bodies [6,7]. In the ME7 model of prion disease, a tractable laboratory model of chronic neurodegeneration, synapse degeneration in the stratum radiatum of the hippocampus is characterised by the degeneration of the pre-synaptic compartment prior to the loss or degeneration of the post-synaptic dendritic spine. Electron microscopy studies reveal degeneration of the pre-synaptic compartment prior to the post-synaptic dendritic spine [6,7] These changes are readily quantified as the degenerating presynaptic terminals appear electron dense, there is loss of vesicle integrity and the post-synaptic density (PSD) becomes progressively curved as it envelops the degenerating presynaptic terminal [7]
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