Cannabinoid receptor 2 evolutionary gene loss makes parrots more susceptible to neuroinflammation.

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 gene that is involved in immune regulation. Notably, we show that the gene pseudogenized in all parrots (Psittaciformes). This gene loss occurred because of chromosomal rearrangements. Our positive selection analysis suggests the absence of any specific molecular adaptations in parrot that would compensate for the 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 gene loss. We compare the expression patterns of CNR and neuroinflammatory markers in -deficient parrots (represented by the budgerigar, and five other parrot species) with -intact passerines (represented by the zebra finch, ). 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 () and 6 ()) in the brain. Our results indicate the functional importance of the gene loss for increased sensitivity to brain inflammation.