The excitatory, glutamatergic input onto MSNs activates AMPA-type glutamate receptors, NMDARs and metabotropic glutamate receptors. Studies of each of these receptor subclasses in the striatum has revealed their importance for striatal function; however, the precise role of each of these receptor types in various forms of learning remains incompletely understood. Throughout the brain, NMDARs are thought to be particularly important in learning due to their long-lasting open times, calcium permeability, and facilitation of long-term potentiation . Both direct and indirect evidence implicates NMDARs in the striatum in several types of learning. In addition to their role in transmitting glutamate signals in mature animals during learning, NMDARs have been implicated in neuronal development in several brain regions. NMDARs are tetramers that require two essential NR1 subunits for assembly of a functional receptor. Mice with a conditional allele of the unique gene Grin1, which encodes the NR1 subunit, have been crossed to mice expressing Cre recombinase selectively in the striatum. The results of these studies have confirmed that NMDAR currents are absent in neurons lacking NR1 and that LTP cannot be elicited in striatal slice preparations from these animals. However, the behavioral consequences differ in these studies, perhaps due to incomplete knockout of striatal NR1 protein in the mice that were less severely affected, or expression of Cre recombinase in striatal interneurons as well as MSNs. We have generated a conditional Grin1 knockout that selectively and completely depletes NMDARs from both populations of MSNs, while leaving those in interneurons intact. These mice have significantly smaller MSNs with shorter dendrites than littermate control mice. Although they are PF-4217903 grossly normal, these knockout mice are completely incapable of several forms of learning. We have generated a genetic mouse model in which Cre recombinase expressed at the Gpr88 locus selectively ablates NR1 expression in all MSNs within the striatum. Others have shown that similar genetic models lack striatal NMDAR currents, and fail to elicit LTP in striatal slice preparations. These findings are in general agreement with a large amount of evidence implicating NMDAR-mediated calcium entry in facilitating LTP in many types of neurons. We have used this model to show that NMDARs on MSNs are required for normal MSN morphology in adult animals. They are not required for survival in our vivarium or for normal 24-hr spontaneous locomotion in mice. However, NMDARs on MSNs are critical for learning in each of the motor, fear, and appetitive tasks that we examined. In addition, NMDARs on MSNs are required for normal MSN morphology in adult animals. The finding that striatal NMDARs are not required for survival or normal baseline functions including baseline locomotion and grip strength is consistent with data from a similar model in which Cre recombinase expressed from the striatum-specific Rgs9 locus was used to inactivate the Grin1 locus.