Insulin has been shown to impact on learning and memory in both humans and animals, but the downstream signaling mechanisms involved are poorly characterized. Insulin receptor substrate-2 (Irs2) is an adaptor protein that couples activation of insulin- and insulin-like growth factor-1 receptors to downstream signaling pathways. Here, we have deleted "Irs2", either in the whole brain or selectively in the forebrain, using the nestin Cre- or D6 Cre-deleter mouse lines, respectively. We show that brain- and forebrain-specific "Irs2" knockout mice have enhanced hippocampal spatial reference memory. Furthermore, "NesCreIrs2KO" mice have enhanced spatial working memory and contextual- and cued-fear memory. Deletion of "Irs2" in the brain also increases PSD-95 expression and the density of dendritic spines in hippocampal area CA1, possibly reflecting an increase in the number of excitatory synapses per neuron in the hippocampus that can become activated during memory formation. This increase in activated excitatory synapses might underlie the improved hippocampal memory formation observed in "NesCreIrs2KO" mice. Overall, these results suggest that "Irs2" acts as a negative regulator on memory formation by restricting dendritic spine generation.