Small intraneuronal acidification via short-chain monocarboxylates: First evidence of an inhibitory action on over-excited human neocortical neurons.

Aims: In cortical mammalian neurons, small fluctuations of intracellular pH (pHi) play a crucial role for inter- and intracellular signaling as well as for cellular and synaptic plasticity. Yet, there have been no respective data about humans. Thus, we investigated the interrelation of pHi and excitability of human cortical neurons.

Materials And Methods: Intracellular electrophysiological and pH-recordings were made in neurons in slices taken from brain tissue resected from the middle temporal gyrus of two male children (26 months and 35 months old) who suffered from pharmacotherapy-resistant temporal lobe epilepsy. To excite the tissue (n = 13), we used the 0-Mg2+/high-K+-in vitro epilepsy model producing robust epileptiform discharges (ED). To evoke an intracellular acidification (n = 12), we used the well-established propionate-model and applied 10 mM propionate to the bath solutions. In addition, we recorded the effects of other strongly related short-chain monocarboxylates (l-lactate (10 mM) and the ketone body DL-β-hydroxybutyrate (10 mM)) on ED and pHi.

Key Findings: The ED-frequency was reversibly reduced by propionate (n = 5), l-lactate (n = 5), or DL-β-hydroxybutyrate (n = 3), while the durations of EDs and their after-depolarizations increased. In parallel experiments, all three short-chain monocarboxylates (each n = 4) lowered the pHi of the neurons (n = 12) by 0.05-0.07 pH units which was temporally related to the reported changes in bioelectric activity.

Significance: A mild drop of the intraneuronal pH was associated with the control of even over-excited human neocortical tissue. This is identical with prior observations in non-human mammalian cortical neurons. Possible implications for neuroplasticity and the treatment of neuropsychiatric disorders are discussed.