Bisphosphate
nucleotidase 2 (BPNT2) is a member of a family of
phosphatases that are directly inhibited by
lithium, the first-line medication for
bipolar disorder. BPNT2 is localized to the Golgi, where it metabolizes the by-products of
glycosaminoglycan sulfation reactions. BPNT2-knockout mice exhibit impairments in total-body chondroitin-4-sulfation which lead to abnormal skeletal development (chondrodysplasia). These mice die in the perinatal period, which has previously prevented the investigation of BPNT2 in the adult nervous system. Previous work has demonstrated the importance of
chondroitin sulfation in the brain, as chondroitin-4-sulfate is a major component of perineuronal nets (PNNs), a specialized neuronal extracellular matrix which mediates synaptic plasticity and regulates certain behaviors. We hypothesized that the loss of BPNT2 in the nervous system would decrease chondroitin-4-sulfation and PNNs in the brain, which would coincide with behavioral abnormalities. We used Cre-lox breeding to knockout Bpnt2 specifically in the nervous system using Bpnt2 floxed (fl/fl) animals and a
Nestin-driven
Cre recombinase. These mice are viable into adulthood, and do not display gross physical abnormalities. We identified decreases in total
glycosaminoglycan sulfation across selected brain regions, and specifically show decreases in chondroitin-4-sulfation which correspond with increases in chondroitin-6-sulfation. Interestingly, these changes were not correlated with gross alterations in PNNs. We also subjected these mice to a selection of neurobehavioral assessments and did not identify significant behavioral abnormalities. In summary, this work demonstrates that BPNT2, a known target of
lithium, is important for
glycosaminoglycan sulfation in the brain, suggesting that
lithium-mediated inhibition of BPNT2 in the nervous system warrants further investigation.