Developmental and age-dependent plasticity of GABAA receptors in the mouse colon: Implications in colonic motility and inflammation

Lifelong functional plasticity of the gastrointestinal (GI) tract is essential for health, yet the underlying molecular mechanisms are poorly understood. The enteric nervous system (ENS) regulates all aspects of the gut function, via a range of neurotransmitter pathways, one of which is the GABA-GABA(A) receptor (GABA(A)R) system. We have previously shown that GABA(A) receptor subunits are differentially expressed within the ENS and are involved in regulating various GI functions. We have also shown that these receptors are involved in mediating stress-induced colonic inflammation. However, the expression and function of intestinal GABA(A)Rs, at different ages, is largely unexplored and was the focus of this study. Here we show that the impact of GABA(A)R activation on colonic contractility changes from early postnatal period through to late adulthood, in an age-dependant manner. We also show that the highest levels of expression for all GABA(A)R subunits is evident at postnatal day (P) 10 apart from the alpha 3 subunit which increased with age. This increase in the alpha 3 subunit expression in late adulthood (18 months old) is accompanied by an increase in the expression of inflammatory markers within the mouse colon. Finally, we demonstrate that the deletion of the alpha 3 subunit prevents the increase in the expression of colonic inflammatory markers associated with healthy ageing. Collectively, the data provide the first demonstration of the molecular and functional plasticity of the GI GABA(A)R system over the course of a lifetime, and its possible role in mediating the age-induced colonic inflammation associated with healthy ageing.