title: Lack of RIC-3 congruence with beta2 subunit-containing nicotinic acetylcholine receptors in bipolar disorder.
abstract: Nicotinic acetylcholine receptor (nAChR) dysfunction occurs in individuals with schizophrenia (SZ) and may also affect individuals with bipolar disorder (BP). The molecular mechanisms for these disease-associated cholinergic deficits are not known. In vitro, the protein RIC-3 (resistance to inhibitors of cholinesterase-3) aids the assembly and trafficking of alpha7-nAChRs but has unclear action on the biogenesis of alpha4/beta2-nAChRs. To evaluate RIC-3/nAChR dynamics in diseased and normal human brain tissue, we measured RIC-3, alpha7-, alpha4- and beta2-nAChRs transcript levels in postmortem prefrontal cortex of individuals with SZ (n=31), BP (n=28) and unaffected controls (NC, n=33). Of the 28 individuals with BP, 20 had a history of psychotic symptoms. We compared relative message abundances between diagnostic groups and tested correlations of RIC-3 with each nAChR message subtype. RIC-3 and alpha4 messages were significantly increased in BP compared with NC (RIC-3, P< or =0.002; alpha4, P< or =0.04). RIC-3 message was also upregulated in SZ (P< or =0.04). In BP with psychoses, RIC-3 and alpha4 levels were increased compared with BP without psychoses (both P< or =0.02) and compared with NC (RIC-3, P< or =0.0003; alpha4, P< or =0.004). In correlation regression analyses, RIC-3 expression was very highly correlated to alpha7, alpha4 and beta2 in NC (alpha7, P< or =2.5e-05; alpha4, P< or =2.5e-09; beta2, P< or =0.003) and in SZ (alpha7, P< or =1e-07; alpha4, P< or =7e-07; beta2, P< or =3e-09). RIC-3 also strongly correlated with alpha7 and alpha4 in BP (alpha7, P< or =0.003; alpha4, P< or =3.5e-07). RIC-3 was modestly correlated with beta2 in BP overall (P< or =0.04), but showed no significant correlation in BP with psychoses (P< or =0.31) compared with a significant correlation in BP without psychoses (P< or =0.007). In conclusion, coordinated RIC-3/alpha4 upregulation and discordant RIC-3/beta2 levels suggest that alpha4/beta2 nAChR deficits in BP may occur from dysregulated RIC-3 chaperoning of the beta2 nAChR subunit in a subset of patients affected by psychotic features.
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Blalock 1105, Baltimore, MD 21287-4933, USA. eseverance@jhmi.edu
authors.forename: E G
authors.initials: EG
authors.lastname: Severance
authors.forename: R H
authors.initials: RH
authors.lastname: Yolken
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012044:Regression Analysis
chemical_list: D014150:Antipsychotic Agents; D047908:Intracellular Signaling Peptides and Proteins; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C496701:RIC3 protein, human