Ventrolateral neurons of medullary organotypic cultures: intracellular pH regulation and bioelectric activity

The hypothesized role of the intracellular pH (pH_i) as a proximate stimulus for central chemosensitive neurons is reviewed on the basis of data obtained from organotypic cultures of the medulla oblongata (obex level) of new born rats (OMC). Within OMC a subset of neurons responds to hypercapnia as do neurons in the same (or similar) brain areas in vivo. Maneuvers altering intra- and/or extracellular pH (pH_o) such as hypercapnia, bicarbonate-withdrawal, or ammonium pre-pulses, evoked well defined changes of the neuronal pH_i. During hypercapnia (pH_o 7.0) or bicarbonate-withdrawal (pH_o 7.4) most ventrolateral neurons adopted a pH_i which was ≤0.2 pH units below the steady state pH_i, while signs of pH_i-regulation occurred only in a small fraction of neurons. During all treatments leading to intracellular acidosis, bioelectric activity of chemosensitive neurons increased and was often indistinguishable from the response to hypercapnia, regardless of whether pH_o was unchanged, decreased or increased during the treatment. These data strongly suggest that the pH_i acts as proximate stimulus. The mode of acid extrusion of chemosensitive neurons is, therefore, of major importance for the control of central chemosensitivity. Immunocytochemical data, pH_i measurements and neuropharmacological studies with novel drugs pointed to the Na⁺/H⁺ exchanger subtype 3 (NHE3) as a main acid extruder in ventrolateral chemosensitive neurons. Possible functions and neuropharmacological strategies arising from this very local NHE3 expression are discussed.