The molecular underpinnings controlling affective behavior remain incompletely understood but human genetics suggests an important role of BDNF. We find that the receptor sortilin, following regulated presynaptic shedding retards the conversion of proBDNF into mature BDNF. Sortilin-deficient mice (Sort1–/–) were devoid of proBDNF-dependent hippocampal LTD and showed reduced excitability in the amygdala, whereas the opposite was true in mice overexpressing the receptor. In both mouse models the aberrant kinetics of proBDNF processing prevented generation of a long-lasting supply of BDNF required to sustain LTP. This translated into a manic and risk-taking behavior in Sort1–/– mice whereas overexpression was associated with traits of anhedonia and anxiety. Collectively, we have identified sortilin as a “thermostat” of glutaminergic plasticity, genetically and functionally linked to mood regulation.