GABA_B Receptor Activation Inhibits Neuronal Excitability and Spatial Learning in the Entorhinal Cortex by Activating TREK-2 K⁺ Channels

The entorhinal cortex (EC) is regarded as the gateway to the hippocampus and thus is essential for learning and memory. Whereas the EC expresses a high density of GABA_B receptors, the functions of these receptors in this region remain unexplored. Here, we examined the effects of GABA_B receptor activation on neuronal excitability in the EC and spatial learning. Application of baclofen, a specific GABA_B receptor agonist, inhibited significantly neuronal excitability in the EC. GABA_B receptor-mediated inhibition in the EC was mediated via activating TREK-2, a type of two-pore domain K⁺ channels, and required the functions of inhibitory G proteins and protein kinase A pathway. Depression of neuronal excitability in the EC underlies GABA_B receptor-mediated inhibition of spatial learning as assessed by Morris water maze. Our study indicates that GABA_B receptors exert a tight control over spatial learning by modulating neuronal excitability in the EC.