Signalling mechanisms in epilepsy and synaptic scaling

Abstract

Background: Neuroplasticity enables the brain to alter its electrophysiological activity depending on stimuli. Neuroplasticity mechanisms often intersect with disease mechanisms. One type is Hebbian plasticity, which is a positive feedback mechanism serving to strengthen or weaken synaptic transmission and is central to learning and memory. Another type is synaptic scaling, which is a negative feedback mechanism that adjusts Hebbian modifications to ensure that net neuronal activity remains at a homeostatic set point. Excessive or reduced neuronal activity triggers synaptic scaling and these activity states induce down or upscaling of synaptic strength to revert to the activity setpoint. Synaptic scaling mechanisms are not yet fully revealed. However, scaling is likely to be highly relevant to disease since malfunction would result in neuronal activity that is excessive or inhibited. Epilepsy is characterised by excessive neuronal activity. In theory, seizures arising from excessive excitation should invoke synaptic downscaling. So the question arises as to whether a malfunctioning downscaling mechanism is involved. Epilepsy develops over time in a process known as epileptogenesis but mechanistic information is lacking to understand the most relevant biological processes.

Method: With our capacity to explore the phosphoproteome and proteome in-depth using mass spectrometry, key phospho-signalling and protein expression events that drive synaptic downscaling and epileptogenesis were determined in mouse models.

Findings: Comparing the phosphoproteomic and proteomic data from both the early epileptogenesis and synaptic downscaling screens we found that down-regulation of synaptic proteins induced synaptic weakening in both models, with subtle differences. Major differences related to broader phospho-regulation of translation in early epileptogenesis, likely driven by activation of additional protein kinases.