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 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.

GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells

“…In the present investigation, we found that hCMEC/D3 cells express the following GABA A receptor subunits: α1 (also confirmed by immunoblotting), α5, β1, β2, and γ1. Therefore, human cerebrovascular endothelial cells possess all the three distinct GABA A receptor subunits that can arrange into a pentameric ion channel with the likely stoichiometry 2α:2β:1γ [ 3 , 6 ]. Based upon their expression levels, GABA A receptors in hCMEC/D3 cells are predicted to incorporate the α1, β1, and γ1 subunits.…”

“…The neurotransmitter γ-aminobutyric acid (GABA) is not only crucial to maintain a proper excitatory:inhibitory balance in neuronal networks by inhibiting glutamatergic pyramidal neurons [ 1 , 2 , 3 ], but is also instrumental to generate synchronized network oscillations that underpin optimal cognitive functions [ 4 , 5 ]. GABA dampens neuronal excitability by gating Cl − -permeable GABA A receptors, thereby enabling Cl − influx down the electrochemical gradient and hyperpolarizing the membrane potential [ 4 ].…”

“…GABA dampens neuronal excitability by gating Cl − -permeable GABA A receptors, thereby enabling Cl − influx down the electrochemical gradient and hyperpolarizing the membrane potential [ 4 ]. GABA A receptors typically consist of pentameric channels formed by the combination of three distinct subunits, according to the following stoichiometry: 2α:2β:1γ [ 3 , 6 ]. GABA-dependent inhibition of neurotransmitter release and neuronal activity may also be mediated by metabotropic G i/o protein–coupled GABA B receptors, which are widely distributed in the central nervous system [ 7 , 8 ].…”

Mechanisms Involved in Epileptogenesis in Alzheimer’s Disease and Their Therapeutic Implications

“…GABAergic dysfunction has gained increasing attention in recent years. In this respect, a significant reduction in GABA concentration in the temporal lobe, selective reduction of GABAergic inhibitory interneurons and a reduction of GABAergic terminals, especially in the areas closest to amyloid plaques, have all been reported in animal models [23,85,93,94]. This decreased GABAergic tone [12] leads to abnormal cortical hypersynchronization and could also decrease neuro and synaptogenesis [93,94].…”

Mechanisms Underlying Cognitive Impairment Induced by Prenatal Alcohol Exposure

“…In experimental animal models, GABA receptor hyperactivation inhibits the release of glutamate and dopamine, thereby reducing the levels of other neurotransmitters linked to behavior modulation through its ability to regulate cognitive function. Further, studies showed that alterations in the expression of GABA receptors in animals impairs memory function [ 102 , 103 ], and prenatal alcohol exposure can chronically alter brain development and function in the offspring [ 104 ]. One study on cortical plate samples from fetal and infant brains demonstrated insufficient and delayed production of GABAergic interneurons in the ganglion during the two first trimesters of pregnancy and their delayed incorporation into the laminar structures of the frontal cortex, as well as mispositioning of GABAergic and calretininergic interneurons throughout fetal life [ 105 ].…”