Abstract Intracellular pH is a potent modulator of neuronal functions. By catalyzing (de)hydration of CO 2 , intracellular carbonic anhydrase (CA i ) isoforms CAII and CAVII contribute to neuronal pH buffering and dynamics. The presence of two highly active isoforms suggests that they form spatially distinct CA i pools enabling subcellular modulation of pH. Here we show that CAVII, unlike CAII, is localized to the filamentous actin network, and its overexpression induces formation of thick actin bundles and membrane protrusions in fibroblasts. In neurons, CAVII is enriched in dendritic spines, and its over-expression causes aberrant spine morphology. We identified amino acids unique to CAVII that are required for direct actin interactions, promoting actin filament bundling and spine targeting. Lack of CAVII in neocortical neurons leads to reduced spine density and increased proportion of small spines. Thus, our work demonstrates highly distinct subcellular expression patterns of CAII and CAVII, and a novel, structural role of CAVII.

Carbonic anhydrase VII regulates dendritic spine morphology and density via actin filament bundling