Endocannabinoids (eCBs) are small molecules that are capable of modulating synaptic plasticity of both excitatory and inhibitory synapses in the brain. While eCBs bind to transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1) in the central nervous system, we recently identified a form of non-CB1, non-TRPV1 mediated long term depression activated by the eCB anandamide at CA1 hippocampal stratum radiatum interneurons. GPR55, an orphan G-protein receptor, has been identified in the hippocampus and is capable of activation by eCBs, making it a good candidate for mediating this non-CB1, non-TRPV1 form of synaptic plasticity. Here we performed whole-cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of GPR55 agonist O-1602 on excitatory synapses. We also performed field recordings from CA1 pyramidal cells in rats and GPR55 knockout mice and littermate controls to investigate the effect of GPR55 agonists O-1602 and lysophosphatidylinositol (LPI) on both basal output and electrically induced long-term depression and long-term potentiation in the hippocampus. Application of O-1602 in rats depressed long-term potentiation in CA1 pyramidal cells, and depressed excitatory glutamatergic transmission onto some interneurons. O-1602 had no effect on long-term depression of CA1 pyramidal cells. GPR55 +/+ mice showed an increase in long-term potentiation in the presence of LPI compared to GPR55-/- littermates. GPR55-/-mice had no change in long-term potentiation when exposed to O-1602, though there was an increase in post-tetanic potentiation with O-1602. In order to examine whether GPR55 has a role in formation of spatial memory, GPR55 -/- mice were compared to littermate controls during a Morris water maze behavioral task, with a reversal task after 7 days of training. GPR55-/-mice did not perform in a different manner on either the training task or the reversal, though there may be a trend of difference in training worth investigating further. This study illustrates a novel pathway for synaptic plasticity modulation through GPR55 in the hippocampus, and may therefore provide valuable insight into both the effects of synthetic and endogenous cannabinoids on the brain and the processes underlying learning and memory.