Lack of RIC-3 congruence with β2 subunit-containing nicotinic acetylcholine receptors in bipolar disorder

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 α7-nAChRs but has unclear action on the biogenesis of α4/β2-nAChRs. To evaluate RIC-3/nAChR dynamics in diseased and normal human brain tissue, we measured RIC-3, α7-, α4- and β2-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 α4 messages were significantly increased in BP compared with NC (RIC-3, P≤0.002; α4, P≤0.04). RIC-3 message was also upregulated in SZ (P≤0.04). In BP with psychoses, RIC-3 and α4 levels were increased compared with BP without psychoses (both P≤0.02) and compared with NC (RIC-3, P≤0.0003; α4, P≤0.004). In correlation regression analyses, RIC-3 expression was very highly correlated to α7, α4 and β2 in NC (α7, P≤2.5e-05; α4, P≤2.5e-09; β2, P≤0.003) and in SZ (α7, P≤1e-07; α4, P≤7e-07; β2, P≤3e-09). RIC-3 also strongly correlated with α7 and α4 in BP (α7, P≤0.003; α4, P≤3.5e-07). RIC-3 was modestly correlated with β2 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/α4 upregulation and discordant RIC-3/β2 levels suggest that α4/β2 nAChR deficits in BP may occur from dysregulated RIC-3 chaperoning of the β2 nAChR subunit in a subset of patients affected by psychotic features.