Heterozygosity of P2RX7 with depression-associated risk allele alters stress response

APRILE GARCÍA, F.; WALSER, S.M.; DEDIC, N.; D., PAEZ PEREDA, M.; JAKUBCAKOVA, V.; STADLER, H.; ACUÑA, M.; WEBB, K.; CZAMARA, D.; LIBERMAN, A. C.; SENIN, S.; GEREZ, J.; HOIJMAN, E.; REFOJO, D.; MITKOVSKI, M.; OLDECAMP, J.; LUCAE, S.; PANHUYSE, M.; SCHMIDT, M.V.; SILLABER, I.; MUELLER-MYHSOK, B.; KIMURA, M.; WURST, W.; STÜHMER, W.; HOLSBOER, F.; ARZT, E.; DEUSSING, J.M.

Capital Federal, Buenos Aires

Simposio; Frontiers in BioScience-Joint Symposium of the Max Planck Society and the Ministry of Science, Technology and Innovation.; 2012

IBioBA MPSP

A single-nucleotide polymorphism in the gene of the purinergic P2X7 receptor (P2X7R) leading to a glutamine (Gln) by arginine (Arg) substitution at codon 460 (Gln460Arg) has been associated with mood disorders. Using transgenic mice in which the murine P2X7R was replaced by the human wild-type or P2X7R-Gln460Arg, respectively, we found that only mice that express both human P2X7R variants showed an altered response to chronic stress and changes in the sleep electroencephalogram equivalent to those of human depression. We further revealed that hetero-oligomerization of wild-type P2X7R with P2X7R-Gln460Arg impairs normal receptor function with respect to calcium intake and intracellular signaling. These results support the notion that heterozygosis of P2X7R with the depression-associated risk allele conveys susceptibility for mood disorders and unravel a molecular basis for the heterozygote disadvantage model.