Physiology & Biophysics

"Metabolic acidosis and the mysterious role of the anion exchanger AE3 in the intracellular-pH physiology of hippocampal neurons and astrocytes"

Ahlam I. Salameh, MS
Physiology & Biophysics
Biomedical Physiology Training Program
Boron Lab
Sept. 6, 2016 3:30 p.m.

School of Medicine E501

Advisor:Walter F. Boron, MD, PhD

Committee:
Dick,Thomas
Egelhoff,Thomas
Ford,Christopher
Schilling,William
Strohl,Kingman
Abstract:

The anion exchanger AE3, expressed in hippocampal (HC) neurons but not astrocytes, contributes to intracellular pH (pHi) regulation by facilitating the exchange of extracellular Cl for intracellular HCO3. The human AE3 polymorphism A867D is associated with idiopathic generalized epilepsy. Moreover, AE3 knockout (AE3–/–) mice are more susceptible to epileptic seizure. The mechanism of these effects has been unclear because the starting pHi in AE3–/– and wild-type neurons is indistinguishable. The purpose of the present study was to use AE3–/– mice to investigate the role of AE3 in pHi homeostasis in HC neurons, co-cultured with astrocytes. We find that the presence of AE3 increases the acidification rate constant during pHi recovery from intracellular alkaline loads imposed by reducing [CO2]. The presence of AE3 also speeds intracellular acidification during the early phase of metabolic acidosis (MAc), not just in neurons but, surprisingly, in adjacent astrocytes. Additionally, AE3 contributes to braking the decrease in pHi later during MAc in both neurons and astrocytes. Paradoxically, AE3 enhances intracellular re-alkalization after MAc removal in neurons and astrocytes, and pHi recovery from an ammonium-prepulse-induced acid load in neurons. The effects of AE3 knockout on astrocytic pHi homeostasis in MAc-related assays require the presence of neurons, and are consistent with the hypothesis that the AE3 KO reduces functional expression of astrocytic NBCe1. These findings suggest a new type of neuron-astrocyte communication, based on the expression of AE3 in neurons, which could explain how AE3 reduces seizure susceptibility.