Abstract
Neuronal hyperexcitability often results from an unbalance between excitatory and inhibitory neurotransmission, but the synaptic alterations leading to enhanced seizure propensity are only partly understood. Taking advantage of a mouse model of neocortical epilepsy, we used a combination of photoconversion and electron microscopy to assess changes in synaptic vesicles pools in vivo. Our analyses reveal that epileptic networks show an early onset lengthening of active zones at inhibitory synapses, together with a delayed spatial reorganization of recycled vesicles at excitatory synapses. Proteomics of synaptic content indicate that specific proteins were increased in epileptic mice. Altogether, our data reveal a complex landscape of nanoscale changes affecting the epileptic synaptic release machinery. In particular, our findings show that an altered positioning of release-competent vesicles represent a novel signature of epileptic networks.
Highlights
Epilepsy is a disorder of the central nervous system that affects around 50 million people worldwide and it is characterized by recurrent spontaneous seizures, that are the clinical manifestation of an excessive hypersynchronous discharge of a population of neurons (Bromfield and Cavazos, 2006)
Our studies included three groups of C57BL/6 mice with injections into the primary visual cortex (V1): a control group injected with vehicle (Control), an Acute epileptic group tested 10 days after Tetanus neurotoxin (TeNT) injection in V1 and a Chronic epileptic group tested 45 days after TeNT injection in V1
Synaptic vesicles from three animals in each of these groups were labeled by infusing FM1-43FX in the visual cortex while presenting a series of visual stimuli (Figure 1A)
Summary
Epilepsy is a disorder of the central nervous system that affects around 50 million people worldwide and it is characterized by recurrent spontaneous seizures, that are the clinical manifestation of an excessive hypersynchronous discharge of a population of neurons (Bromfield and Cavazos, 2006). Recent technological advances have allowed a detailed characterization of the size and spatial organization of functional vesicle pools. These parameters correlate with measures of synaptic strength and are altered following plasticity-inducing stimuli (Rey et al, 2020). Such ultrastructural readouts of Synaptic Vesicles Dynamics in Epilepsy synaptic function have not been applied far to the study of epileptogenic modifications or their consequences
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