Acid-base imbalance leads to pathological cognition and behaviors in the clinical practices. In the comparison with acidosis, the cellular mechanisms underlying alkalosis-induced brain dysfunction remain unclear. By using electrophysiological approach, we investigated the influences of high extracellular pH environment on cortical GABAergic neurons in terms of their responsiveness to synaptic inputs and their ability to produce action potentials. Artificial cerebral spinal fluid in high pH impairs excitatory synaptic transmission and spike initiation in cortical GABAergic neurons. The alkalosis-induced dysfunction of GABAergic neurons is associated with the decrease of receptor responsiveness and the increases of spike refractory periods and threshold potentials. Our studies reveal that alkalosis impairs cortical GABAergic neurons and subsequently deteriorate brain functions. The molecular targets for alkalosis action include glutamate receptor-channels and voltage-gated sodium channels on GABAergic neurons. (C) 2012 Elsevier Inc. All rights reserved.