Role of Heparin-Binding Growth-Associated Molecule (HB-GAM) in Hippocampal LTP and Spatial Learning Revealed by Studies on Overexpressing and Knockout Mice

Abstract

Heparin-binding growth-associated molecule (HB-GAM) is an extracellular matrix-associated protein with neurite outgrowth-promoting activity and which is suggested to be implicated in hippocampal synaptic plasticity. To study the functions of HB-GAM in adult brain we have produced HB-GAM overexpressing mice and compared phenotypic changes in the transgenic mice to those in the HB-GAM null mice. Both mutants were viable and displayed no gross morphological abnormalities. The basal synaptic transmission was normal in the area CA1 of hippocampal slices from the genetically modified mice. However, long-term potentiation (LTP) was attenuated in the mice overexpressing HB-GAM, whereas enhanced LTP was detected in the HB-GAM-deficient mice. Changes in LTP seen in vitro were paralleled by behavioral alterations in vivo. The animals overexpressing HB-GAM displayed faster learning in water maze and decreased anxiety in elevated plus-maze, while the HB-GAM knockouts demonstrated an opposite behavioral phenotype. These results show that HB-GAM suppresses LTP in hippocampus and plays a role in regulation of learning-related behavior.