Cannabinoid receptor 2 evolutionary gene loss makes parrots more susceptible to neuroinflammation Divin, Daniel Gómez Samblás, María Mercedes Kuttiyarthu Veetil, Nithya Voukali, Eleni Swiderska, Zuzana Krajzingrova, Teresa Martin, Tesicky Vladimir, Benes Elleder, Daniel Bartos, Oldrich Vinkler, Michal neuroimmunology avian immunology cannabinoid receptors neural inflammation gene loss cannabinoid receptor pseudogenization In vertebrates, cannabinoids modulate neuroimmune interactions through two cannabinoid receptors (CNRs) conservatively expressed in the brain (CNR1, syn. CB1) and in the periphery (CNR2, syn. CB2). Our comparative genomic analysis indicates several evolutionary losses in the CNR2 gene that is involved in immune regulation. Notably, we show that the CNR2 gene pseudogenized in all parrots (Psittaciformes). This CNR2 gene loss occurred because of chromosomal rearrangements. Our positive selection analysis suggests the absence of any specific molecular adaptations in parrot CNR1 that would compensate for the CNR2 loss in the modulation of the neuroimmune interactions. Using transcriptomic data from the brains of birds with experimentally induced sterile inflammation we highlight possible functional effects of such a CNR2 gene loss. We compare the expression patterns of CNR and neuroinflammatory markers in CNR2-deficient parrots (represented by the budgerigar, Melopsittacus undulatus and five other parrot species) with CNR2-intact passerines (represented by the zebra finch, Taeniopygia guttata). Unlike in passerines, stimulation with lipopolysaccharide resulted in neuroinflammation in the parrots linked with a significant upregulation of expression in proinflammatory cytokines (including interleukin 1 beta (IL1B) and 6 (IL6)) in the brain. Our results indicate the functional importance of the CNR2 gene loss for increased sensitivity to brain inflammation. 2025-01-20T07:36:52Z 2025-01-20T07:36:52Z 2022-11-09 journal article Divín D et al. 2022 Cannabinoid receptor 2 evolutionary gene loss makes parrots more susceptible to neuroinflammation. Proc. R. Soc. B 289: 20221941. https://doi.org/10.1098/rspb.2022.1941 https://hdl.handle.net/10481/99574 10.1098/rspb.2022.1941 eng GAUK 646119 PRIMUS/17/SCI/12 START/SCI/113 with reg. no. CZ.02.2.69/0.0/0.0/19_073/0016935 Czech Science Foundation grant no. P502/19-20152Y Institutional Research Support grant no. 260571/2022 http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional