In the brain there exists a fine balance between excitation and inhibition of neurons. This depends largely on the activity of neurotransmitters and their receptors, at synapses. Glutamate is the major excitatory neurotransmitter, whilst GABA is the main inhibitory neurotransmitter. In order to function properly, each
neurotransmitter must combine with an appropriate receptor. Abnormal increases / decreases in glutamate / GABA levels respectively (or in the number of their available receptors), can cause neurons to become hyperexcitable and susceptible to seizures.

Cellular prion protein (PrPc) is encoded by a gene known as PRNP, and is found in a number of organs, including the brain. Here it has been shown to have various roles, including the maturation and protection of neurons; but its effects on neurotransmission are not clear.

Researchers at the Institute for Bioengineering of Catalonia (IBEC) and the University of Barcelona (UB) have recently explored this function of PrPc and made some important findings.

The aim of the study was to look at the effects of both an excess and a lack of PrPc on three outcomes - seizure activity, cell death, and gene expression - in living epilepsy models. In order to do this the team bred three populations of animals - a control group, in which all members carried normal (wild-type) PrPc; a group that had had the PRNP gene removed and so couldn't produce PrPc (these were called prnp -/-); and group that produced too much PrPc (known as the Tg20 group).

Kainic acid (KA) is a compound that is very similar to glutamate, and it can be used experimentally to excite neurons. In the brain it combines to two very closely related glutamate receptors, known as AMPA and kainate.

The scientists treated the three animal groups with KA, to compare their susceptibility to seizures, and found that the prnp -/- group showed an increased susceptibility to KA compared to the wild-type population (i.e. their seizure threshold had decreased).

Interestingly, the Tg20 group demonstrated even more susceptibility to seizures than their prnp -/- counterparts. This was unexpected, because, as mentioned earlier, normal PrPc has a protective effect on neurons. It would make sense, therefore, that an increase in the amount of PrPc would give even more of a neuro-protective effect. However this was not the case.

The team then examined the link between altered PrPc levels and neurotransmitter function more closely. Using advanced analysis techniques, they looked at the activity of the GABA, AMPA and kainate receptor genes in all three animal populations. Sure enough, in both the prnp -/- and Tg20 groups, the activity of these genes, and therefore the number of GABA, AMPA and kainate receptors present in the brain were significantly altered.

These findings are exciting, because they suggest that a normal level of PrPc is essential in preserving the excitation-inhibition balance in the brain and preventing seizures - something that was not known before. If abnormal PrPc is also found to cause seizures in humans, new treatments that counteract the adverse effects and mimic normal PrPc function could be developed in the future.

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