Significance G protein-coupled receptors constitute an important class of receptors and represent a family of choice for therapeutic interventions for multiple diseases and disorders. One of these metabotropic glutamate receptors, mGluR5, is highly relevant because of its biological importance for various medical conditions, including major depressive disorder (MDD). In a search of mGluR5 modulators we identified Norbin as a key regulator. Here we demonstrate in vivo that Norbin significantly influences hippocampal neurogenesis and that both the proliferation and survival of newborn neurons are impaired in the absence of Norbin. Furthermore, the use of three well-established behavioral paradigms indicated that Norbin-KO mice display depressive-like characteristics. Thus interventions that could boost Norbin function might be beneficial to treat MDD symptoms.