Sa2050 Corticotropin-Releasing Factor (CRF) Peptides Modulates Rat Colonic Neuronal Tau Phosphorylation: Differential Role of CRF Receptors

BACKGROUND: Corticotropin releasing factor receptor-1 (CRF1)-overexpression enhances experimental stress or CRF-induced tau (TAU) phosphorylation in the mouse brain (PNAS, 2012: 109(16):6277-82). CRF is a key mediator of the gut response to stress. Whether CRF affect enteric TAU and whether enteric neuronal TAU modulation impacts gastrointestinal tract functions are not known. AIM: 1) Determine 1) the effect of selective activation of CRF receptors on rat colon primary myneteric neuron Tau 2) the colonic motor response of Tau transgenic mice to acute stress. METHODS: Rat distal colonic primary myenteric neurons were incubated with non-selective CRF1 and 2 receptor agonists (CRF, urocortin 1 (Ucn1)) and selective CRF2 receptor agonist (Ucn2) for 30 min (10 or 100 nM) and pTAU probed by western blot. Rat colon primary myenteric neurons were processed for immunostaining of Tau. Human TauP301L overexpressing and wild-type (WT) mice were exposed to 1-hour novel environment stress and cumulative Fecal Pellet Output (FPO) at 5, 15, 30, 45 and 60 min was monitored. The overexpression of human Tau in the TauOE mice was confirmed by western blotting. RESULTS: Rat colon primary neurons have constitutively active pTau that is suppressed by selective CRF2 receptor activation but not by the non-selective CRF receptor ligand, CRF. Rat colon primary myenteric neurons have abundant Tau. Compared to WT, Tau overexpressing mice have 2-4X increased total Tau mRNA expression, increased defecation (60.7±6.5% increase in 60 min cumulative FPO) response to mild novel environment stress and display altered ileal and colonic CRF2 receptor expression. CONCLUSION: The differential modulation of colonic primary myenteric TAU phophorylation by CRF peptides and the altered colonic motor response to stress in the mice that express phospho TAU in the intestine and the modulation of colonic CRF2 receptor mRNA profile in these mice, suggest a possible interplay between myenteric TAU and CRFsignaling in the colonic response to stress. Supported by R01DK078676 (MM); Veterans Administration Merit Review (MEH-W)