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


RESULTS
In cortical membrane preparations, GluA1 and pGluA1Ser(831) 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 pGluA1Ser(831) expression was observed in rCC membrane preparations in rats pre-exposed to acid neonatally followed by adult rechallenge.


CONCLUSIONS
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.
Division of Gastroenterology & Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
B
B
Banerjee
Division of Gastroenterology & Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
B K
BK
Medda
Division of Gastroenterology & Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
J
J
Zhang
University of Wisconsin, Oshkosh, WI, USA.
V
V
Tuchscherer
Division of Gastroenterology & Hepatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
R
R
Babygirija
Division of Gastroenterology & Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
P
P
Kannampalli
Division of Gastroenterology & Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
J N
JN
Sengupta
Division of Gastroenterology & Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
R
R
Shaker
D000818:Animals; D002540:Cerebral Cortex; D015536:Down-Regulation / Q000187:drug effects*; D005744:Gastric Acid; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
D018091:Receptors, AMPA
AMPA receptor subunits; cortical sensitization; esophageal hypersensitivity; homeostatic plasticity; synaptic scaling