Calcineurin Aγ is a Functional Phosphatase That Modulates Synaptic Vesicle Endocytosis

Variation in PPP3CC, the gene that encodes the gamma isoform of the calcineurin catalytic subunit, has been reported to be associated with schizophrenia. Because of its low expression level in most tissues, there has been little research devoted to the specific function of the calcineurin A gamma (CNA gamma) versus the calcineurin A alpha (CNA alpha) and calcineurin A beta (CNA beta) catalytic isoforms. Consequently, we have a limited understanding of the role of altered CNA gamma function in psychiatric disease. In this study, we demonstrate that CNA gamma is present in the rodent and human brain and dephosphorylates a presynaptic substrate of calcineurin. Through a combination of immunocytochemistry and immuno-EM, we further show that CNA gamma is localized to presynaptic terminals in hippocampal neurons. Critically, we demonstrate that RNAi-mediated knockdown of CNA gamma leads to a disruption of synaptic vesicle cycling in cultured rat hippocampal neurons. These data indicate that CNA gamma regulates a critical aspect of synaptic vesicle cycling and suggest that variation in PPP3CC may contribute to psychiatric disease by altering presynaptic function.