Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene

Abstract

The choroid plexus (CP) forms the blood‐cerebrospinal fluid (CSF) barrier (BCSFB) and protects the brain from circulating drugs and toxins. Plasma membrane monoamine transporter (PMAT, SLC29A4) is a novel polyspecific monoamine and organic cation (OC) transporter. Here we investigated the role of PMAT in CP transport of endogenous amines and xenobiotic cations. The mRNA expression of PMAT and functionally related transporters, including the classic monoamine transporters (SERT, DAT, NET) and the OC transporters (OCT1~3, MATE1/2), were measured in human and mouse CPs. The expression and membrane localization of the PMAT protein were determined by immunostaining. A mouse model with targeted deletion of the Slc29a4 gene was generated and validated. The significance of PMAT in CP uptake of monoamines/OCs was evaluated in uptake assays using CPs from wild type and Pmat−/−mice. Our results showed that PMAT is the predominant OC/monoamine transporter in the CP and is localized to the CSF‐facing apical membrane of the CP epithelium. Pmat−/−mice are viable, fertile with no overt physiological abnormalities. Importantly, Pmat−/−CPs showed much reduced (~30–40%) uptake of monoamines/OCs. There was no significant involvement of other tested transporters. Together our data demonstrated that PMAT transports monoamines/OCs from the CSF into the CP and mediates the first step of monoamine/OC brain efflux at the BCSFB.This work was supported by NIH Grants GM066233 and GM066233–07S1.