Abstract:GABA (gamma-aminobutyric acid) is the main inhibitory transmitter in the adult brain, and it exerts its fast hyperpolarizing effect through activation of anion (predominantly Cl-)-permeant GABA(A) receptors. However, during early neuronal development, GABA(A)-receptor-mediated responses are often depolarizing, which may be a key factor in the control of several Ca2+-dependent developmental phenomena, including neuronal proliferation, migration and targeting. To date, however, the molecular mechanism underlying… Show more
“…These findings indicate that NKCC1 and KCC2 underlie the opposing responses to glycine in zebrafish THNs, similar to the situation described in mammalian models [7,15]. In this speculative model, newly emerging THNs inherit NKCC1 from precursor cells and therefore exhibit higher intracellular Cl − levels (Figure 3(a)).…”
Section: Resultssupporting
confidence: 78%
“…From > 28 hpf onwards, KCC2 is expressed. This reduces the intracellular Cl − concentration, so that glycine receptor opening results in an influx of Cl − from the extracellular space ([15], Figure 3(c)), which leads to hyperpolarization, and THN speed decrease.10.1080/19420889.2018.1493324-F0003Figure 3.Model showing how NKCC1/KCC2 co-expression with different glycine receptor strength can regulate THN speed. (a) THNs in phase 1 express NKCC1 (yellow), while KCC2 (brown) becomes expressed only in differentiating phase 2 THNs.…”
Section: Resultsmentioning
confidence: 99%
“…It is thought that regular depolarization via glycine and NKCC1 is necessary to maintain the proliferation of neuronal precursors [11–13]. The hyperpolarizing effect of glycine in mature neurons in contrast [14,15] depends on the co-expression of KCC2 ( slc12a5b ) [15,16]. KCC2 lowers the intracellular Cl − concentration, which causes an influx of Cl − opening of the glycine receptor, and membrane hyperpolarization.…”
Various neurotransmitters influence neuronal migration in the developing zebrafish hindbrain. Migrating tegmental hindbrain nuclei neurons (THNs) are governed by depolarizing neurotransmitters (acetylcholine and glutamate), and glycine. In mature neurons, glycine binds to its receptor to hyperpolarize cells. This effect depends on the co-expression of the solute carrier KCC2. Immature precursors, however, typically express NKCC1 instead of KCC2, leading to membrane depolarization upon glycine receptor activation. As neuronal migration occurs in neurons after leaving the cell cycle and before terminal differentiation, we hypothesized that the switch from NKCC1 to KCC2 expression could alter the effect of glycine on THN migration. We tested this notion using in vivo cell tracking, overexpression of glycine receptor mutations and whole mount in situ hybridization. We summarize our findings in a speculative model, combining developmental age, glycine receptor strength and solute carrier expression to describe the effect of glycine on the migration of THNs.
“…These findings indicate that NKCC1 and KCC2 underlie the opposing responses to glycine in zebrafish THNs, similar to the situation described in mammalian models [7,15]. In this speculative model, newly emerging THNs inherit NKCC1 from precursor cells and therefore exhibit higher intracellular Cl − levels (Figure 3(a)).…”
Section: Resultssupporting
confidence: 78%
“…From > 28 hpf onwards, KCC2 is expressed. This reduces the intracellular Cl − concentration, so that glycine receptor opening results in an influx of Cl − from the extracellular space ([15], Figure 3(c)), which leads to hyperpolarization, and THN speed decrease.10.1080/19420889.2018.1493324-F0003Figure 3.Model showing how NKCC1/KCC2 co-expression with different glycine receptor strength can regulate THN speed. (a) THNs in phase 1 express NKCC1 (yellow), while KCC2 (brown) becomes expressed only in differentiating phase 2 THNs.…”
Section: Resultsmentioning
confidence: 99%
“…It is thought that regular depolarization via glycine and NKCC1 is necessary to maintain the proliferation of neuronal precursors [11–13]. The hyperpolarizing effect of glycine in mature neurons in contrast [14,15] depends on the co-expression of KCC2 ( slc12a5b ) [15,16]. KCC2 lowers the intracellular Cl − concentration, which causes an influx of Cl − opening of the glycine receptor, and membrane hyperpolarization.…”
Various neurotransmitters influence neuronal migration in the developing zebrafish hindbrain. Migrating tegmental hindbrain nuclei neurons (THNs) are governed by depolarizing neurotransmitters (acetylcholine and glutamate), and glycine. In mature neurons, glycine binds to its receptor to hyperpolarize cells. This effect depends on the co-expression of the solute carrier KCC2. Immature precursors, however, typically express NKCC1 instead of KCC2, leading to membrane depolarization upon glycine receptor activation. As neuronal migration occurs in neurons after leaving the cell cycle and before terminal differentiation, we hypothesized that the switch from NKCC1 to KCC2 expression could alter the effect of glycine on THN migration. We tested this notion using in vivo cell tracking, overexpression of glycine receptor mutations and whole mount in situ hybridization. We summarize our findings in a speculative model, combining developmental age, glycine receptor strength and solute carrier expression to describe the effect of glycine on the migration of THNs.
“…The switch in polarity of inhibitory signalling from depolarising to hyperpolarising during development depends on changes in the homeostasis of Cl the major ion passing through GABA operated channels. The expression of KCC2, the K-Cl transporter (Payne et al, 1996), at several days after birth causes a hyperpolarising shift in Cl reversal potential thus switching GABAergic signalling to its adult inhibitory function (Rivera et al 1999).…”
Section: Does An Epileptic Brain Emerge From Developmental and Repairmentioning
Focal epilepsies of the mesial temporal lobe are often associated with a hippocampal sclerosis. Changes in Cl homeostasis and GABAergic signalling in downstream regions, may contribute to the human pathology. A review of changes in cellular and synaptic function and connectivity after de-afferentation suggests this epileptic syndrome may involve a pathological replay of developmental mechanisms.
“…During neuronal maturation a switch from excitatory to inhibitory actions of GABA and glycine was observed (Rivera et al 1999). In mature neurons, the neuronal K + / Cl ¡ -cotransporter 2 (KCC2) carries molar ratios of K + and Cl ¡ -ions across the neuronal plasma membrane, leading to the extrusion of Cl ¡ from the cell interior and thus shifting the Cl ¡ -equilibrium to more negative values.…”
Section: Excitatory Glyr Function and Cellular Signalingmentioning
Synapses can be considered chemical machines, which are optimized for fast and repeated exocytosis of neurotransmitters from presynaptic nerve terminals and the reliable electrical or chemical transduction of neurotransmitter binding to the appropriate receptors in the postsynaptic membrane. Therefore, synapses share a common repertoire of proteins like, e.g., the release machinery and certain cell adhesion molecules. This basic repertoire must be extended in order to generate speciWcity of neurotransmission and allow plastic changes, which are considered the basis of developmental and/or learning processes. Here, we focus on these complementary molecules located in the presynaptic terminal and postsynaptic membrane specializations of glycinergic synapses. Moreover, as speciWcity of neurotransmission in this system is established by the speciWc binding of the neurotransmitter to its receptor, we review the molecular properties of glycine receptor subunits and their assembly into functional glycine receptors with diVerent functional characteristics. The past years have revealed that the molecular machinery underlying inhibitory and especially glycinergic postsynaptic membrane specializations is more complex and dynamic than previously anticipated from morphological studies. The emerging features include structural components as well as signaling modules, which could confer the plasticity required for the proper function of distinct motor and sensory functions.
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