Synaptic Vesicles Dynamics in Neocortical Epilepsy

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.

Role of Clathrin and Dynamin in Clathrin Mediated Endocytosis/Synaptic Vesicle Recycling and Implications in Neurological Diseases

“…Affecting ~50 million people worldwide, epilepsy is a central nervous system disorder with spontaneous seizures as the main symptom (Li et al, 2015 ; Vannini et al, 2020 ). In lesional epilepsy, seizures develop in response to brain damage (Pitkänen and Immonen, 2014 ), while in non-lesional epilepsy they are the result of altered synaptic function (Farisello et al, 2013 ; Vannini et al, 2020 ). These seizures are caused by high frequency, synchronous and uncontrolled synaptic transmission in the brain (Li et al, 2015 ; Vannini et al, 2020 ).…”

“…In lesional epilepsy, seizures develop in response to brain damage (Pitkänen and Immonen, 2014 ), while in non-lesional epilepsy they are the result of altered synaptic function (Farisello et al, 2013 ; Vannini et al, 2020 ). These seizures are caused by high frequency, synchronous and uncontrolled synaptic transmission in the brain (Li et al, 2015 ; Vannini et al, 2020 ). SVR plays a clear role in this abnormal synaptic transmission by maintaining the neurotransmission of the central synapses (Li et al, 2015 ).…”

“…In addition there is significant evidence of dynamins role in epileptic seizures (Anggono et al, 2006 ; Appenzeller et al, 2014 ). Mutations in dynamin 1 have been observed to cause epileptic symptoms, while in both animal models and human epilepsy dynamin 1 is upregulated and may contribute to the development of seizures, with dynamin inhibition, by the small molecule inhibitor Dynasore, exhibiting anti-epileptic effects (Appenzeller et al, 2014 ; Li et al, 2015 ; Vannini et al, 2020 ). Moreover the clinically used levetiracetam (Keppra TM ) is believed to act directly at synaptic vessel protein 2 (SV2A) (Lynch et al, 2004 ; Klein et al, 2020 ; Contreras-García et al, 2021 ).…”

Glutamate’s Secret Interictal Life

“…Indeed, another recent study found altered synaptic vesicle dynamics that were inhibitory or excitatory synapse-specific in the tetanus toxin epilepsy mouse model. 10 This, combined with the increasing number of genetic variants that cause epilepsy found in synaptic vesicle associated proteins (e.g., DNM1 , STXBP1 , and SNAP25 ) makes it clear that the relevance of presynaptic vesicle dynamics to seizure occurrence is a topic worthy of further inquiry.…”

The role of peptidyl-prolyl isomerase Pin1 in neuronal signaling in epilepsy

“…Neurotransmitters and neuroendocrine axes are critical in the onset of epilepsy ( Camfield et al, 2017 ). Although the molecular mechanism of epilepsy has not been fully elucidated, there is growing evidence for synaptic transmission in the pathological process of epilepsy ( Amador et al, 2020 ; Puhahn-Schmeiser et al, 2021 ), and altered dynamics of inhibitory synapses and excitatory synapses may be a critical signature of epileptic networks ( Vannini et al, 2020 ).…”