GRK3 deficiency elicits brain immune activation and psychosis.
Carl M SellgrenSophie ImbeaultMarkus K LarssonAlfredo OliverosIda A K NilssonSimone CodeluppiFunda OrhanMaria BhatMaximilian Tufvesson-AlmJessica GraciasMagdalena E KegelYiran ZhengAnthi FakaMarie SvedbergSusan B PowellSorana CaldwellMary E KamenskiMarquis P VawterAnton SchulmannMichel GoinyCamilla I SvenssonTomas HökfeltMartin SchallingLilly SchwielerSimon CervenkaDoo-Sup ChoiMikael LandénGöran EngbergSophie ErhardtPublished in: Molecular psychiatry (2021)
The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3-/- mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3-/- mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.
Keyphrases
- bipolar disorder
- major depressive disorder
- poor prognosis
- prefrontal cortex
- high fat diet induced
- binding protein
- resting state
- white matter
- electronic health record
- spinal cord
- endothelial cells
- functional connectivity
- type diabetes
- long non coding rna
- small molecule
- neuropathic pain
- photodynamic therapy
- bone mineral density
- tyrosine kinase
- spinal cord injury
- adipose tissue
- body composition
- blood brain barrier
- drug induced
- data analysis
- replacement therapy
- pluripotent stem cells
- deep learning