Prolonged esophageal acid exposures induce synaptic downscaling of cortical membrane AMPA receptor subunits in rats

Abstract

Background we recently reported the involvement of AMPA receptor subunit upregulation and phosphorylation in the rostral cingulate cortex (rCC) as the underlying mechanism of acute esophageal acid-induced cortical sensitization. Based on these findings we proposed to investigate whether prolonged esophageal acid exposures in rats exhibit homeostatic synaptic scaling through downregulation of AMPA receptor expression in rCC neurons. We intended to study further whether this compensatory mechanism is impaired when rats are preexposed to repeated esophageal acid exposures neonatally during neuronal development. Methods two different esophageal acid exposure protocols in rats were used. Since AMPA receptor trafficking and channel conductance depend on CaMKIIα-mediated phosphorylation of AMPA receptor subunits, we examined the effect of esophageal acid on CaMKIIα activation and AMPA receptor expression in synaptoneurosomes (SYNs) and membrane preparations from rCCs. Key Results in cortical membrane preparations, GluA1 and pGluA1Ser831 expression were significantly downregulated following prolonged acid exposures in adult rats, this was accompanied by a significant downregulation of cortical membrane pCaMKIIα expression. No change in GluA1 and pGluA1Ser831 expression was observed in rCC membrane preparations in rats preexposed to acid neonatally followed by adult rechallenge. Conclusions & Inferences this study along with our previous findings suggests that synaptic AMPA receptor subunits expression and phosphorylation may be involved bidirectionally in both esophageal acid-induced neuronal sensitization as well as acid-dependent homeostatic plasticity in cortical neurons. The impairment of homeostatic compensatory mechanism as observed following early-in-life acid exposure could be the underlying mechanism of heightening cortical sensitization and esophageal hypersensitivity in patients with GERD.