Significance of GABAA Receptor for Cognitive Function and Hippocampal Pathology.

Yuya Sakimoto,Paw Min-Thein Oo,Makoto Goshima,Dai Mitsushima,Itsuki Kanehisa,Yutaro Tsukada

doi:10.3390/ijms222212456

Yuya Sakimoto, Paw Min-Thein Oo + Show 4 more

Open Access

https://doi.org/10.3390/ijms222212456

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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 GABAA (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABAA 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 GABAA 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 GABAA receptor trafficking, synaptic E/I imbalance and neuronal excitability.

Highlights

The hippocampal cornu ammonia 1 (CA1) region has a total number of 350,000 neurons within a range from 320,000 to 380,000 at postnatal day 30 in Wistar rats [1]
We found a rapid increase in mEPSC amplitude within 5 min after inhibitory avoidance (IA) training, showing that memory encoding rather than retrieval strengthens AMPA receptor-mediated excitatory synapses
As to the causal relationship between learning and plasticity, we previously reported that bilateral expression of GluA1-containing AMPA receptor delivery blockers in CA1 neurons impairs IA learning [26]

Summary

Introduction

The hippocampal CA1 region has a total number of 350,000 neurons within a range from 320,000 to 380,000 at postnatal day 30 in Wistar rats [1]. Gamma-aminobutyric acid (GABA) ergic interneurons contain a conservative estimate of ~38,500 inhibitory interneurons in the CA1 region [2,3] According to their molecular signatures, GABAergic interneurons can be divided into five main groups: Parvalbumin, somatostatin, neuropeptide Y, vasoactive intestinal peptide and cholecystokinin interneuron [4,5]. While excitatory inputs target a distal dendric spine of a CA1 pyramidal neuron, inhibitory inputs are largely concentrated in the perisomatic region. From this distribution of excitatory and inhibitory inputs, a potent perisomatic inhibition is considered to control dendritic excitatory inputs and play an important role in the decision-making of pyramidal cell activation itself [6]

The GABAergic System

Contextual Fear Memory Triggers Rapid Synaptic Plasticity

Intracellular Mechanism of Rapid Inhibitory Synaptic Plasticity

Alterations to GABAARβ3 in Cognitive Disease

Conclusions