Significance of GABAA Receptor for Cognitive Function and Hippocampal Pathology

Abstract

The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABA_A (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABA_A receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABA_A receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer's disease, autism spectrum disorders and epilepsy are characterized by alterations in GABA_A receptor trafficking, synaptic E/I imbalance and neuronal excitability.

Keywords: AMPA receptor; GABAA receptor; contextual learning; synaptic plasticity.

Figure 1

Schematic image of CA1 pyramidal neurons. IA training rapidly strengthened GABA_A receptor-mediated inhibitory synapses within 1 min, while the training strengthened AMPA receptor-mediated excitatory synapses within 5 min. CA1 pyramidal neurons exhibited broad diversity of excitatory/inhibitory synaptic currents within 5 min, and the neuron-specific synaptic diversity was sustained for more than 60 min.

Figure 2

Schematic image of GABA_A receptor trafficking mechanisms. The phosphorylation in the β₃ subunit Ser^408–409 increased levels of GABA_A receptors at post-synapses, resulting an increase in mIPSC. Since IA training facilitated the phosphorylation in the β₃ subunit (Ser^408–409) and GABA_A receptor-mediated current within 1 min, we suggested that the rapid inhibitory plasticity may contribute to maintaining memory function in hippocampus.