Hippocampus Insulin Receptors Regulate Episodic and Spatial Memory Through Excitatory/Inhibitory Balance

It is well known that the hippocampus is a vital brain region playing a key role in both episodic and spatial memory. Insulin receptors (InsRs) are densely distributed in the hippocampus and are important for its function. However, the effects of InsRs on the function of the specific hippocampal cell types remain elusive. In this study, hippocampal InsRs knockout mice had impaired episodic and spatial memory. GABAergic neurons and glutamatergic neurons in the hippocampus are involved in the balance between excitatory and inhibitory (E/I) states and participate in the processes of episodic and spatial memory. InsRs are located mainly at excitatory neurons in the hippocampus, whereas 8.5% of InsRs are glutamic acid decarboxylase 2 (GAD2)::Ai9-positive (GABAergic) neurons. Next, we constructed a transgenic mouse system in which InsR expression was deleted from GABAergic (glutamate decarboxylase 2::InsR(fl/fl), GAD2(Cre)::InsR(fl/fl)) or glutamatergic neurons (vesicular glutamate transporter 2::InsR(fl/fl),Vglut2(Cre)::InsR(fl/fl)). Our results showed that in comparison to the InsR(fl/fl) mice, both episodic and spatial memory were lower in GAD2(Cre)::InsR(fl/fl) and Vglut2(Cre)::InsR(fl/fl). In addition, both GAD2(Cre)::InsR(fl/fl) and Vglut2(Cre)::InsR(fl/fl) were associated with more anxiety and lower glucose tolerance. These findings reveal that hippocampal InsRs might be crucial for episodic and spatial memory through E/I balance hippocampal regulation.