Childhood adversity interacts with purinergic receptor polymorphism, influencing depression and anxiety scores D. Kovacs 1,2, X. Gonda 1,2,3, N. Eszlari 1,2, D. Pap 1,2, G. Bagdy 1,2, G. Juhasz 1,2,4 1 Semmelweis University, Budapest, Hungary 2 Hungarian Academy of Sciences, Budapest, Hungary 3 National Institute of Psychiatry and Addictions, Budapest, Hungary 4 University of Manchester, UK

Introduction Actions of extracellular ATP mediated by: -Metabotropic P2Y receptors -Ionotropic P2X receptors ( /~biochem/f or748/images/stories/tp10_abb1_neu.jp g) Functions of the P2RX7: -Regulating the activation and proliferation of microglia. -Providing necessary co- stimulus for IL-1β release in inflammatory response and host-defense reaction -Altering psychological stress reactivity -”Danger signal”, contributing to neuronal death, influencing neuroplasticity P2RX7 mechanisms of action: -Ligand mediated cation chanel -Non-selective pore forming if the activation is persistent -Increased Glutamate release induced by Ca 2+ influx (Sperlagh et al. 2012)

Introduction Single nucleotide polymorphisms in the P2RX7 gene found to be associated with: -Chronic lymphocitic leukemia -Pulmonary tubercolosis -Osteoporosis -Multiple sclerosis -Systemic lupus erythematosus -Ischemic stroke -Chronic inflammatory and neuropathic pain -Major and bipolar depression -Anxiety disorders (Jiang et al. 2013) -P2RX7 null-mutant mice shows reduced pain sensitivity -rs minor (His) allele in humans was reported to affect alodynia in a large osteoarthritis patient group -The polymorphism disables the pore-forming function of the P2RX7 receptors, exerting neuroprotective effects, and suppressing the development of pain sensitivity. (Sorge et al. 2013)

Objectives -Examine the role of rs polymorphism at the development of depression and anxiety. -Find possible interactions with environmental factors, such as stressfull life events. Methods Population sample: non-related individuals from Manchester and Budapest -740 men, 1702 women -Caucasian origin Measured phenotypes: -Depression and anxiety scores by the Brief Symptom Inventory (BSI) questionaire -Recent life events by List of Life threatening experiences (RLE) -Childhood adversity by Childhood Trauma Questionnaire (CHA)

Results -AA genotype only showed protective function against depression if severe childhood maltreatment was absent. - There were no significant interactions with recent life events.

Results -Childhood abuse abolished the protective effect of the AA genotype against anxiety -Interction was not observable with recent life events

Conclusions -Just like in the case of chronic pain, the protective function of the minor allele was presented in depression and anxiety. -This protective effect is sensitive to early, but not to recent life stressors. -Our findings emphasize the role of P2RX7 in brain development and neuroplasticity, possibly through the disabled pore-forming. References -SPERLAGH, B., CSOLLE, C., ANDO, R. D., GOLONCSER, F., KITTEL, A. & BARANYI, M The role of purinergic signaling in depressive disorders. Neuropsychopharmacol Hung, 14, JIANG, L. H., BALDWIN, J. M., ROGER, S. & BALDWIN, S. A Insights into the Molecular Mechanisms Underlying Mammalian P2X7 Receptor Functions and Contributions in Diseases, Revealed by Structural Modeling and Single Nucleotide Polymorphisms. Front Pharmacol, 4, 55. -SORGE, R. E., TRANG, T., DORFMAN, R., SMITH, S. B., BEGGS, S., RITCHIE, J., AUSTIN, J. S., ZAYKIN, D. V., VANDER MEULEN, H., COSTIGAN, M., HERBERT, T. A., YARKONI-ABITBUL, M., TICHAUER, D., LIVNEH, J., GERSHON, E., ZHENG, M., TAN, K., JOHN, S. L., SLADE, G. D., JORDAN, J., WOOLF, C. J., PELTZ, G., MAIXNER, W., DIATCHENKO, L., SELTZER, Z., SALTER, M. W. & MOGIL, J. S Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med, 18,