A prion regulates neurotransmitter balance; excessive levels cause epilepsy
Kofi
Discovery of New Function of Prion Protein Improves Understanding of
Epilepsy
ScienceDaily (Dec. 31, 2009) � Cellular prion protein (PrPc) plays an
essential role in maintaining neurotransmitter homeostasis in the
central nervous system. This discovery has been made possible by the
observation that both a deficiency and an excess of the protein have a
considerable effect on this homeostasis. Surprisingly, in both cases,
the central nervous excitability threshold is altered to such an extent
that an epileptic seizure may result. Thanks to this discovery, we now
have more tools at our disposal that can help us to deepen our basic
understanding of epilepsy.
The discovery, carried out by researchers of the Institute for
Bioengineering of Catalonia (IBEC) and the University of Barcelona (UB),
led by Jos� Antonio Del R�o, with the collaboration of researchers at
Pablo de Olavide University and the National Institute for Food and
Agriculture Technology Research, was presented in a study published in
PLoS ONE.
Neurotransmitter homeostasis is achieved through a balance between those
mechanisms that excite the neurons of the central nervous system and
those that inhibit them. In the study, it was observed in laboratory
animals that when PrPc is absent, the excitatory mechanisms are altered
and epileptic seizures may occur. As under normal conditions the protein
is found in adequate concentrations, it was expected that greater
amounts of PrPc would provide greater protection against seizures..
Surprisingly, however, the study showed that this is not the case. With
an excessive amount of the protein, the level of excitability of the
central nervous system is increased even more than in the absence of
PrPc, due to the fact that both the excitatory and inhibitory mechanisms
are altered. Such alterations further increase the possibility of
suffering severe epileptic seizures. These results allow us to conclude
that the protein, when present at adequate concentrations, is essential
for maintaining neurotransmitter homeostasis or equilibrium in the
central nervous system.
The researchers of IBEC and the UB who participated in the study are
currently involved in developing a description of the possible
differences in the expression and modification of the cellular prion
protein in epileptic patients.
Gene Regulation
The study published in PLoS ONE also found a correlation between the
differential susceptibility induced by alterations in PrPc levels and
the gene expression of the excitatory and inhibitory neurotransmitter
receptors of the cerebral cortex. It was conducted using transcriptomic
microarray analysis, which made it possible to identify a set of 129
co-regulated genes in the absence and overexpression of the protein in
the brains of laboratory animals. The analysis of the canonical pathways
associated with these co-regulated genes and its subsequent validation
made it possible for the first time to determine that both the absence
and the overexpression of PrPc affect the levels of expression of
glutamate receptors (AMPA-Kainate -- an excitatory neurotransmitter) and
of GABA (GABAA -- an inhibitory neurotransmitter). Finally, the effects
of the differential regulation were corroborated by electrophysiological
techniques that are pioneering in Spain.
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Story Source:
Adapted from materials provided by IBEC - Institute for Bioengineering
of Catalonia, via AlphaGalileo.
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Journal Reference:
1. Alejandra Rangel, Noelia Madro�al, Agn�s Gruart i Mass�, Rosalina
Gav�n, Franc Llorens, Lauro Sumoy, Juan Mar�a Torres, Jos� Mar�a
Delgado-Garc�a, Jos� Antonio Del R�o. Regulation of GABAA and Glutamate
Receptor Expression, Synaptic Facilitation and Long-Term Potentiation in
the Hippocampus of Prion Mutant Mice. PLoS ONE, 2009; 4 (10): e7592 DOI:
10.1371/journal.pone.0007592