A Shared Vesicular Carrier Allows Synaptic Corelease of GABA and Glycine

Wojcik, Sonja M.; Katsurabayashi, Shutaro; Guillemin, Isabelle; Friauf, Eckhard; Rosenmund, Christian; Brose, Nils; Rhee, Jeong−Seop

doi:10.1016/j.neuron.2006.04.016

Cited by 334 publications

(354 citation statements)

References 57 publications

(85 reference statements)

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“…S1 J, S7D, available at www.jneurosci.org as supplemental material). Together with previous work (Ludwig et al, 2003;Titz et al, 2003;Wojcik et al, 2006), our results do not support a role of depolarizing GABA in inducing KCC2 expression, an effect previously reported in cultured neurons (Ganguly et al, 2001). , and Olig1 (found in independent screen) at different ages during development (normalized to WT Ϯ SEM; n Ͼ 3 animals per genotype and age).…”

Section: Delayed Maturation Of Glutamatergic and Gabaergic Transmissicontrasting

confidence: 52%

NKCC1-Dependent GABAergic Excitation Drives Synaptic Network Maturation during Early Hippocampal Development

Pfeffer¹,

Stein²,

Keating³

et al. 2009

J. Neurosci.

129

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A high intracellular chloride concentration in immature neurons leads to a depolarizing action of GABA that is thought to shape the developing neuronal network. We show that GABA-triggered depolarization and Ca 2ϩ transients were attenuated in mice deficient for the Na-K-2Cl cotransporter NKCC1. Correlated Ca 2ϩ transients and giant depolarizing potentials (GDPs) were drastically reduced and the maturation of the glutamatergic and GABAergic transmission in CA1 delayed. Brain morphology, synaptic density, and expression levels of certain developmental marker genes were unchanged. The expression of lynx1, a protein known to dampen network activity, was decreased. In mice deficient for the neuronal Cl Ϫ /HCO 3 Ϫ exchanger AE3, GDPs were also diminished. These data show that NKCC1-mediated Cl Ϫ accumulation contributes to GABAergic excitation and network activity during early postnatal development and thus facilitates the maturation of excitatory and inhibitory synapses.

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Section: Delayed Maturation Of Glutamatergic and Gabaergic Transmissicontrasting

confidence: 52%

NKCC1-Dependent GABAergic Excitation Drives Synaptic Network Maturation during Early Hippocampal Development

Pfeffer¹,

Stein²,

Keating³

et al. 2009

J. Neurosci.

129

View full text Add to dashboard Cite

show abstract

“…106,155,156 This filling process, however, requires activity of a vacuolar H þ -ATPase that provides the electrical (DC) and chemical (DpH) components of the driving force for the vesicular inhibitory amino-acid transporter. 147,157 After release to the synaptic cleft, re-uptake of GABA occurs via Na þ -/Cl À -dependent GABA transporter 1 in the presynaptic terminal or via GAT-3 in processes of astrocytes that enwrap the synapse. Again, these processes are secondarily active, thus utilizing potential energy that has been previously provided by the Na þ /K þ -ATPase and other transport systems.…”

Section: Energy Utilization Of Fast-spiking Behavior and Synaptic Inhmentioning

confidence: 99%

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

Kann

Papageorgiou

Draguhn

2014

J Cereb Blood Flow Metab

212

235

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Gamma oscillations (B30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency ('fast-spiking') and synchronize the activity of numerous pyramidal cells by rhythmic inhibition ('clockwork'). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and g-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited ('interneuron energy hypothesis'). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.

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“…Changes in the function or expression of these transporters can modify the quantal size of synaptic potentials. 319 Plasma membrane transporters regulate the activity of neurotransmitters including GABA and biogenic amines by sequestering them into cells after they are released from nerve terminals. They couple transmembrane movement of Na ϩ and Cl Ϫ (and in some systems, K ϩ ) to the reuptake of the neurotransmitter.…”

Section: Neurotransmitter Transportersmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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A Shared Vesicular Carrier Allows Synaptic Corelease of GABA and Glycine

Cited by 334 publications

References 57 publications

NKCC1-Dependent GABAergic Excitation Drives Synaptic Network Maturation during Early Hippocampal Development

NKCC1-Dependent GABAergic Excitation Drives Synaptic Network Maturation during Early Hippocampal Development

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

Molecular Targets for Antiepileptic Drug Development

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