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

Abstract

Background

We recently reported the involvement of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 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 pre-exposed 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 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 the significant downregulation of cortical membrane pCaMKIIα expression. No change in GluA1 and pGluA1Ser⁸³¹ expression was observed in rCC membrane preparations in rats pre-exposed 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 and 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 gastroesophageal reflux disease.

The findings of this study provide a better understanding of the esophageal pain mechanisms for patients with gastroesophageal reflux disease. The main objective was to investigate whether prolonged esophageal acid exposures in Sprague Dawley rats resulted in homeostatic synaptic scaling through downregulation of cortical AMPA receptor membrane expression.

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