LACK OF RIC-3 CONGRUENCE WITH BETA2 SUBUNIT-CONTAINING NICOTINIC ACETYLCHOLINE RECEPTORS IN BIPOLAR DISORDER
Neuroscience. 2007 Jul 18; [Epub ahead of print]
Severance EG, Yolken RH
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
Nicotinic acetylcholine receptor (nAChR) dysfunction occurs in individuals with schizophrenia (SZ) and may also affect individuals with bipolar disorder (BP). The molecular mechanism 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=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 alpha 4 messages were significantly increased in BP compared with NC (RIC-3, P=0.002; alpha4, P=0.04). RIC-3 message was also upregulated in SZ (P=0.04). In BP with psychoses, RIC-3 and alpha4 levels were increased compared with BP without psychoses (both P=0.02) and compared with NC (RIC-3, P=0.0003; alpha4, P=0.004). In correlation regression analyses, RIC-3 expression was very highly correlated to alpha7, alpha4 and beta2 in NC (alpha7, P=2.5e-05; alpha4, P=2.5e-09; beta2, P=0.003) and in SZ (alpha7, P=1e-07; alpha4, P=72-07; beta2, P=3e-09). RIC-3 also strongly correlated with alpha7 and alpha4 in BP (alpha7, P=0.003; alpha4, P=3.5e-07). RIC-3 was modestly correlated with beta2 in BP overall (P=0.04), but showed no significant correlation in BP with psychoses (P=0.31) compared with a significant correlation in BP without psychoses (P=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.