NELL2 is a neuron-specific thrombospondin-1-like extracellular protein containing six epidermal growth factor-like domains and is highly expressed in the hippocampus. We have previously shown that NELL2 promotes survival of neurons through mitogen-activated protein kinases. To clarify the function of NELL2 in vivo, we have generated a novel strain of mice with a targeted mutation in the NELL2 gene and assessed long-term potentiation (LTP) in vivo in the dentate gyrus of NELL2-deficient mice using extracellular recording techniques. Production of LTP at perforant path-granule cell synapses was significantly larger in NELL2-deficient mice than in wild-type controls. Thus, we propose that NELL2 plays an important role as a novel suppressor in LTP in vivo in the mouse dentate gyrus.