Activity of hippocampal formation is finely tuned by a balance between glutamatergic and GABAergic network. Recently, it has been reported that an imbalance of the GABAergic network cause the impairment of memory function as well as adult neurogenesis in Alzheimer's disease (AD) model mice. However, the cause of this dysfunction of GABAergic transmission has been still unclear. In this study, we used APPswe/PSEN1ΔE9 AD model mice feeding with High Fat Diet. This AD model mice showed disorder in cognitive function and adult neurogenesis as early as 6 months old. The purpose of this research is to elucidate the possible reasons of a cause of GABAergic network impairment.
Hippocampal GABAergic activity is regulated by several endogenous molecules. Diazepam binding inhibitor (DBI; also known as ACBP; acyl-CoA Binding Peptide) is an endogenous GABA inverse agonist. In this AD model mice, glial expression of DBI was increased in the hippocampus, especially around senile plaques. In addition, the result from microarray analysis showed elevated expression of both glial GABA-transporters GAT2 (Slc6a13) and BGT1 (Slc6a12) in this type 2 diabetes-AD model mice. Since, elevated expression of DBI and GABA-transporters in glial cells of the hippocampus may interfere with post-synaptic GABAergic transmission; therefore, these alterations would be causes for GABAergic network impairment in AD model mice. We found that the treatment of this AD model mice with a 6 weeks administration of β-alanyl-L-histidine suppressed the elevated expression of DBI and GABA-transporters in glial cells and ameliorated the declines of memory function as well as adult neurogenesis in this type 2 diabetes-Alzheimer's model mice.