Diana Cunha-Reis, Principal Investigator at the Gene Expression and Regulation Group, at Ciências ULisboa, published a new paper, first-authored  by José Rosa, MSc student from the same group, in Frontiers in Cellular Neuroscience, on which the authors conclude that certain lipid molecules present in the structures responsible for the communication between neurons can be the key for developing therapies to prevent epilepsy.

What was the starting point that led to the current research?

Synaptic and neuronal plasticity are a basic feature of brain function, but this can be profoundly altered in diseases like epilepsy. In epileptogenesis research this is usually investigated from a structural point of view, by addressing the changes in the morphology of brain neuronal networks and synaptic contacts. Nonetheless synaptic plasticity can occur also without significant morphological changes, eliciting mostly alterations in the levels and functionality of synaptic receptors and ion channels. Maladaptive changes occurring in these processes early following putative epilepsy-triggering events could greatly contribute to epileptogenesis even in the absence of significant neuronal death or morphologic alterations in neural tissue.

What is the main finding reported in this paper?

In this paper we demonstrate that synaptic plasticity is impaired following two types of epileptiform activity (seizure-like events). We also found alterations in several synaptic receptors and ion channels that may be either contributing to dysfunctional synaptic communication or instead be involved in endogenous neuroprotective responses. In particular, protein lipid raft markers are strongly reduced at hippocampal synapses following seizure-like events. Given the importance of lipid rafts as synaptic signalling platforms this may in turn drive enhanced recruitment of other glutamatergic and GABAergic structural postsynaptic molecules leading to subsequent epileptogenic synaptic changes.

If you had to explain the main finding to a 5-year-old child, how would you do it? 

To be able to communicate well, neurons the most important cells in our brain, have to be positioned correctly. At their point of communication (a cellular structure called synapse), there are even tinier components (molecules) that allow neurons to communicate precisely. If these are misplaced, gone, or crowding all in the same place, neurons cannot function adequately. In epilepsy, neurons are very loud and restless, and we wanted to find out how this comes about. A few of these components, that put all the pieces in place at synapses, are not doing their job well in situations that can bring about epilepsy. We need to find out more about this to find a way to prevent this disease.

Why is it important for the scientific community and for society at large?

Epilepsy, and in particular hippocampal-related mesial temporal lobe epilepsy (MTLE) is a huge burden to society due to its high propensity to develop resistance to antiseizure drugs. This leads to the necessity to perform surgical removal of epileptic tissue but is also associated high mortality due to uncontrolled seizures, including seizure-related accidents. Preventing epileptogenesis, and finding molecular targets to handle this, is one of the most promising approaches in MTLE treatment, since once ongoing, the disease process cannot be reverted.

What are the next steps?

The next steps are to understand exactly where at synapses are lipid rafts altered and how can we induce a fast recovery of lipid raft function. This will involve different experimental approaches, that will allow us to monitor hippocampal responses and hippocampal synapses in vitro but also to study these alterations in the context of the synaptic substructure.

Figure: In the initial hours following neuronal hyperactive states, there is an impairment in synaptic communication and alterations in the molecular composition of synapses (the main spot of neuronal communication). One of these changes pertains the lipid composition and organization of synapses, that in turn conditions the anchoring and retaining of other components essential for synaptic communication and adaptation. These extent of these alterations and of the susceptibility to engage in epileptogenesis is directly related to the intensity of these initial hyperactive states. [from the paper]

Find out more about GER Group  here. 

Read the full paper here.