Insulin-like growth factor-I (IGF-I) exerts multiple actions, yet the role of IGF-I from different sources is poorly understood. Here, we explored the functional and behavioral consequences of the conditional deletion ofIgf-Iin the nervous system (Igf-I^Δ/Δ), and demonstrated that long-term potentiation was impaired in hippocampal slices. Moreover,Igf-I^Δ/Δmice showed spatial memory deficits in the Morris water maze, and the significant sex-dependent differences displayed byIgf-I^Ctrl/Ctrlmice disappeared inIgf-I^Δ/Δmice in the open field and rota-rod tests. BrainIgf-Ideletion disorganized the granule cell layer of the dentate gyrus (DG), and it modified the relative expressions of GAD and VGLUT1, which are preferentially localized to inhibitory and excitatory presynaptic terminals. Furthermore,Igf-Ideletion altered protein modules involved in receptor trafficking, synaptic proteins, and proteins that functionally interact with estrogen and androgen metabolism. Our findings indicate that brain IGF-I is crucial for long-term potentiation, and that it is involved in the regulation of spatial memory and sexual dimorphic behaviors, possibly by maintaining the granule cell layer structure and the stability of synaptic-related protein modules.