Inhibitory synaptic transmission tuned by Ca²⁺ and glutamate through the control of GABA_AR lateral diffusion dynamics

Abstract

The GABAergic synapses, a primary inhibitory synapse in the mammalian brain, is important for the normal development of brain circuits, and for the regulation of the excitation‐inhibition balance critical for brain function from the developmental stage throughout life. However, the molecular mechanism underlying the formation, maintenance, and modulation of GABAergic synapses is less understood compared to that of excitatory synapses. Quantum dot‐single particle tracking (QD‐SPT), a super‐resolution imaging technique that enables the analysis of membrane molecule dynamics at single‐molecule resolution, is a powerful tool to analyze the behavior of proteins and lipids on the plasma membrane. In this review, we summarize the recent application of QD‐SPT in understanding of GABAergic synaptic transmission. Here we introduce QD‐SPT experiments that provide further insights into the molecular mechanism supporting GABAergic synapses. QD‐SPT studies revealed that glutamate and Ca2+ signaling is involved in (a) the maintenance of GABAergic synapses, (b) GABAergic long‐term depression, and GABAergic long‐term potentiation, by specifically activating signaling pathways unique to each phenomenon. We also introduce a novel Ca2+ imaging technique to describe the diversity of Ca2+ signals that may activate the downstream signaling pathways that induce specific biological output.

Nogo-A Modulates the Synaptic Excitation of Hippocampal Neurons in a Ca2+-Dependent Manner

“…While this observation indicates that an influx of extracellular Ca 2+ may underlie the alterations observed in GABA A R dynamics, it did, so far, not exclude that release from the internal stores may contribute to the increase in cytoplasmic Ca 2+ concentration. This question is of relevance since it has been shown that cytoplasmatic Ca 2+ can have different effects on synaptic regulation depending on where it comes from [ 6 ]. While Ca 2+ release from the endoplasmic reticulum (ER) suppressed GABA A R lateral diffusion [ 8 ], Ca 2+ influx through the plasma membrane leads to an increase in their lateral diffusion [ 8 , 54 ].…”

“…Indeed, the strength of inhibitory synaptic transmission depends on the number of gamma-aminobutyric acid receptors (GABA A Rs) present at synapses [ 5 ]. The synaptic localization of GABA A Rs is, in turn determined both by their clustering via synaptic scaffold proteins as well as by the control of their lateral diffusion through changes in the intracellular Ca 2+ concentration [ 6 ]. Indeed, the number of GABA A Rs accumulating at the synapse has been shown to depend on the release of Ca 2+ from the internal stores via activation of the IP3R1 and PKC [ 7 , 8 ].…”

Trans-differentiation of Jdp2-depleted Gaba-receptor-positive cerebellar granule cells to Purkinje cells

“…A previous study demonstrated that the Gaba receptor is involved in the regulation of the differentiation of rodent neural progenitor cells [18]. The Gaba receptor is a G-protein-coupled receptor that is associated with inositol 1,4,5-triphosphate (IP3)-induced Ca 2+ signals [20,21,22]. We hypothesized that the Gaba-receptor-mediated Ca 2+ signals are involved in Jdp2-regulated neural differentiation.…”

Biophysical elucidation of neural network and chemical regeneration of neural tissue

“…19 e190024_2 cells with high sensitivity, leading to an understanding of the mechanisms of pathology. Dr. Hiroko Bannai (Waseda University) will talk about the current status, problems, and potential of single-molecule imaging studies in neurological disease research [8,9].…”

“…In recent years, single-molecule imaging plays an important role that contributes to the detection of abnormalities in disease model cells with high sensitivity, leading to an understanding of the mechanisms of pathology. Dr. Hiroko Bannai (Waseda University) will talk about the current status, problems, and potential of single-molecule imaging studies in neurological disease research [ 8 , 9 ].…”