The dopaminergic system in the central nervous system is recognized to play an important role in synaptic plasticity and learning, and is involved in the pathogenesis of a variety of neurological and psychiatric disorders. We show in the present study in mice, similar to what has earlier been reported in rats, that there is a higher density of dopaminergic fibers in stratum oriens (OR) than in stratum radiatum (RAD) within the CA1 region of the dorsal hippocampus. Furthermore, we examined the effect of the D1/5 agonist SKF38393 on NMDAR-dependent LTP in OR and RAD in four week-old mice. In single CA1 neurons, the presence of SKF38393 strongly and selectively reduced LTP in OR. This compartment-specific effect was caused by a Dopamine (DA) agonist-boosted inactivation of synaptic NMDAR-mediated currents (NMDA EPSCs) during LTP induction through a Ca2+-dependent, and G-protein independent mechanism. To analyze NMDAR subtype-specific contributions, we employed two gene-targeted mouse lines. In mice in which NR2A is constitutively ablated (NR2A-/-), the compartment-specific DA agonist-mediated effect on NMDA EPSCs and LTP persisted. In contrast, in mice which lack NR2B in principal forebrain neurons (NR2BDFb), the DA agonist-mediated effects were absent. This indicates that dopaminergic modulation of synaptic efficacy occurs via NMDARs containing NR2B subunits in stratum oriens. Thus, a DA hyperfunction in stratum oriens may result in NMDAR hypofunction that could have an impact on both normal and pathological conditions.