Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex.
Human mesial temporal lobe epilepsies (MTLE) are the most frequent form of partial epilepsies and display frequent pharmacoresistance. The molecular alterations underlying human MTLE remain poorly understood. A two-step transcriptional analysis consisting in cDNA microarray experiments followed by quantitative RT-PCR validations was performed. Because the entorhinal cortex (EC) plays an important role in the pathophysiology of the MTLE and usually discloses no detectable or little cell loss, resected EC and each corresponding lateral temporal neocortex (LTC) of MTLE patients were used as the source of disease-associated and control RNAs, respectively. Six genes encoding (i) a serotonin receptor (HTR2A) and a neuropeptide Y receptor type 1 (NPY1R), (ii) a protein (FHL2) associating with the KCNE1 (minK) potassium channel subunit and with presenilin-2 and (iii) three immune system-related proteins (C3, HLA-DR-gamma and CD99), were found consistently downregulated or upregulated in the EC of MTLE patients as compared with non-epileptic autopsy controls. Quantitative western blot analyses confirmed decreased expression of NPY1R in all eight MTLE patients tested. Immunohistochemistry experiments revealed the existence of a perivascular infiltration of C3 positive leucocytes and/or detected membrane attack complexes on a subset of neurons, within the EC of nine out of eleven MTLE patients. To summarize, a large-scale microarray expression study on the EC of MTLE patients led to the identification of six candidate genes for human MTLE pathophysiology. Altered expression of NPY1R and C3 was also demonstrated at the protein level. Overall, our data indicate that local dysregulation of the neurotransmission and complement systems in the EC is a frequent event in human MTLE.
Jamali
Sarah
S
INSERM UMR 491, Université de la Méditerranée, France.
Bartolomei
Fabrice
F
Robaglia-Schlupp
Andrée
A
Massacrier
Annick
A
Peragut
Jean-Claude
JC
Régis
Jean
J
Dufour
Henri
H
Ravid
Rivka
R
Roll
Patrice
P
Pereira
Sandrine
S
Royer
Barbara
B
Roeckel-Trevisiol
Nathalie
N
Fontaine
Marc
M
Guye
Maxime
M
Boucraut
José
J
Chauvel
Patrick
P
Cau
Pierre
P
Szepetowski
Pierre
P
D000328:Adult; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism*; D015938:Complement Membrane Attack Complex; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D018728:Entorhinal Cortex / Q000276:immunology / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015854:Up-Regulation
D003176:Complement C3; D015938:Complement Membrane Attack Complex; D018377:Neurotransmitter Agents; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor