Extracellular
proton concentrations in the brain may be an important signal for neuron function.
Proton concentrations change both acutely when synaptic vesicles release their acidic contents into the synaptic cleft and chronically during
ischemia and
seizures. However, the brain receptors that detect
protons and their physiologic importance remain uncertain. Using organotypic hippocampal slices and biolistic transfection, we found the
acid-sensing ion channel 1a (ASIC1a), localized in dendritic spines where it functioned as a
proton receptor. ASIC1a also affected the density of spines, the postsynaptic site of most excitatory synapses. Decreasing ASIC1a reduced the number of spines, whereas overexpressing ASIC1a had the opposite effect. Ca(2+)-mediated
Ca(2+)/calmodulin-dependent protein kinase II (
CaMKII) signaling was probably responsible, because
acid evoked an ASIC1a-dependent elevation of spine intracellular Ca(2+) concentration, and reducing or increasing ASIC1a levels caused parallel changes in
CaMKII phosphorylation in vivo. Moreover, inhibiting
CaMKII prevented ASIC1a from increasing spine density. These data indicate that ASIC1a functions as a postsynaptic
proton receptor that influences intracellular Ca(2+) concentration and
CaMKII phosphorylation and thereby the density of dendritic spines. The results provide insight into how
protons influence brain function and how they may contribute to pathophysiology.