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 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.

Key words: human RIC3 protein; alpha4beta2 nicotinic receptor; alpha7 nicotinic receptor; nicotine; antipsychotic agents

Abbreviations: ABI, Applied Biosystems; BP, bipolar disorder; CHRNA4, alpha4 subunit of the nicotinic acetylcholine receptor; CHRNA7, alpha7 subunit of the nicotinic acetylcholine receptor; CHRNB2, beta2 subunit of the nicotinic acetylcholine receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; nAChR, nicotinic acetylcholine receptor; NC, normal control; pmi, postmortem interval; qRT-PCR, quantitative real-time polymerase chain reaction; RIC-3, resistance to inhibitors of cholinesterase-3; SZ, schizophrenia

Article Outline

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