Insulin-like Growth Factor Binding Protein-3 Affects Behavior Activity through Monoaminergic Function and Synaptic Formation

Background: Insulin-like growth factor binding protein-3 (IGFBP3) regulates IGF bioactivity, induces apoptosis and inhibits cell growth independent of IGFs, but the functional role of IGFBP3 in the brain is unknown.

Objective: We clarified the effect of IGFBP3 on the brain by characterizing the phenotype of igfbp3-null mice.

Methods and Results: We established Igfbp3-null mice and used no mutated littermates as wild-type control mice. Compared to wild-type mice, Igfbp3-null mice showed significantly decreased IGF-1 content in the brain but showed no change in weights of brain and body. In igfbp3-null mice the number of dendritic spines was significantly reduced, and the dendritic diameter was thin. In addition, in igfbp3-null mice, a decrease in phosphorylated Akt and ERK1/2 significantly reduced PSD-95 expression, and GAD65/67 expression was significantly decreased. These results indicate that IGFBP3 deficiency impairs neuronal structure and signaling. In behavioral studies, igfbp3-null mice were hyperactive, and a Y-maze alternation test revealed impaired spatial working memory, but no anxiety-like behavior. Monoaminergic analysis using HPLC indicated that igfbp3-null mice showed lower levels of dopamine and serotonin compared to wild-type mice, suggesting an abnormal monoaminergic neurotransmission.

Conclusion: The studies demonstrated that the deletion of IGFBP3 results in behavioral impairments that are associated with abnormal synaptic function and monoaminergic neurotransmission, which helps to characterize the critical role of IGFBP3 in the brain.