Research led by Cardiff University has identified a new potential drug target for the treatment of absence seizures.Grant type: project grantLead Investigators: Professor Vincenzo Crunelli and Professor Giuseppe Di GiovanniLead institution: Cardiff UniversityScientific title: Serotonergic modulation of absence seizures: focus on GABAA inhibition in the thalamusBackgroundExcitation, inhibition and seizure developmentThere is a fine balance in the brain between excitation and inhibition, and this vital for normal function. The major excitatory and inhibitory systems in the brain are called glutamate and GABA respectively, and there is another system known as the serotonin system that regulates the two. All three systems exert their effects via structures called receptors.Seizures are thought to happen when there is an abnormal increase in excitation in the brain, which can be due to either an increase in glutamate activity or a decrease in GABA activity.Absence seizuresAbsence seizures are characterised by a sudden interruption of activity, brief loss of consciousness and a blank stare. They are a feature of many idiopathic (of unknown cause) generalised epilepsies, but their underlying mechanisms are not fully understood and anti-epileptic drug (AED) treatment is only effective in 50-80% of people affected.In the centre of the brain is a structure called the thalamus, which relays nerve messages to and from the cortex (the folded surface of the brain). It also helps to regulate sleep, consciousness and alertness, and it is thought to be important in the generation of absence seizures.Existing evidenceIn a previous study, Professor Crunelli and colleagues discovered a new form of GABA activity called ‘tonic GABAA inhibition’, which was increased in the thalamus of animal models of absence epilepsy. Importantly, they found that this increased tonic GABAA inhibition was necessary for absence seizures to occur. This was somewhat unexpected (it is usually increased excitation that is the suspected culprit); however it has been shown elsewhere.In light of these findings, the team suggested that, in principle, it should be possible to block this GABAA inhibition with drugs and prevent seizures from occurring; however existing therapies would not be selective enough and would also disrupt the ‘normal’ GABA inhibition (causing unwanted side effects).The current studyIn the current project, the group planned to use the latest experimental and behavioural techniques to confirm whether thalamic serotonin is also abnormal in models of absence epilepsy (as well as tonic GABAA inhibition) and, if so, whether serotonin-based therapies could be used modulate tonic GABAA inhibition indirectly.Key findings During the course of the study the researchers made the following key findings:
- serotonin distribution is indeed abnormal in experimental models of absence epilepsy
- serotonin can successfully be used to modulate GABAA inhibition
- targeting the serotonin system can reduce spontaneous absence seizures in a recognised animal model of absence epilepsy
Interestingly, two of the (many) serotonin receptors through which serotonin acts were found to be particularly effective in decreasing absence seizures in freely moving animals; but one of these (known as the ‘serotonin’ 2C receptor) was deemed more suitable as a potential treatment target due to fewer undesirable side effects.SignificanceThese findings are highly significant, because they increase our understanding of absence epilepsy and its underlying mechanisms. This understanding has enabled the researchers to discover a new treatment target, which will hopefully pave the way for the development of more effective therapies in the near future.Professor Crunelli commented: “This grant has allowed our team take a huge step forward in the understanding of absence seizures and the pathological role of serotonin, and this is fundamental to the future development of better treatments.”Click here to see our full portfolio of research grants.