Fluctuation in extracellular pH occurs during normal brain function and pH has been shown to modulate neuronal activity. The acid-sensing ion channels (ASICs) are members of the DEG/ENaC family and are transiently activated by a fall of extracellular pH. In the central nervous system,functional ASICs form homo- and heterotrimers consistingof ASIC1a, ASIC2a and ASIC2b subunits. The loss of ASIC1a eliminates pH-evoked transient inward currents from voltage-clamped neurons and ASIC1^-/- mice showimpaired spatial learning, memory and fear conditioning. To test whether ASIC1a transduces extracellular pH changes into modulation of action potential generation, brain neurons obtained from wild-type and ASIC1^-/- mice were exposed to low pH and whole-cell patch-clamp was used to compare pH-dependent effects on action potential generation. In current clamp mode, acid application depolarized membrane voltage and elicited a brief train of action potentials in wild-type neurons. In ASIC1^-/- neurons, low pH had little if any effect on membrane potential. Under acidic conditions, action potential frequency, amplitude, number, and duration were similar between wild-type and ASIC1^-/- neurons. However, prolonged acidosis elevated the firing threshold of cortical wild-type neurons but not in ASIC1^-/- neurons. Furthermore, we found that acutely dissociated hippocampal interneurons have larger H⁺-gated current densities than pyramidal neurons and that moderate reductions in pH stimulated firing in these inhibitory neurons. These findings suggest that ASIC1a contributes to pH-dependent modulation of neuronal activity.