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1.
J Cell Biol ; 203(2): 283-98, 2013 Oct 28.
Article in English | MEDLINE | ID: mdl-24165939

ABSTRACT

Several studies have suggested that the V0 domain of the vacuolar-type H(+)-adenosine triphosphatase (V-ATPase) is directly implicated in secretory vesicle exocytosis through a role in membrane fusion. We report in this paper that there was a rapid decrease in neurotransmitter release after acute photoinactivation of the V0 a1-I subunit in neuronal pairs. Likewise, inactivation of the V0 a1-I subunit in chromaffin cells resulted in a decreased frequency and prolonged kinetics of amperometric spikes induced by depolarization, with shortening of the fusion pore open time. Dissipation of the granular pH gradient was associated with an inhibition of exocytosis and correlated with the V1-V0 association status in secretory granules. We thus conclude that V0 serves as a sensor of intragranular pH that controls exocytosis and synaptic transmission via the reversible dissociation of V1 at acidic pH. Hence, the V-ATPase membrane domain would allow the exocytotic machinery to discriminate fully loaded and acidified vesicles from vesicles undergoing neurotransmitter reloading.


Subject(s)
Exocytosis , Neurons/enzymology , Secretory Vesicles/enzymology , Synaptic Transmission , Synaptic Vesicles/enzymology , Vacuolar Proton-Translocating ATPases/metabolism , Animals , Catecholamines/metabolism , Cattle , Chromaffin Cells/enzymology , Chromaffin Cells/metabolism , Exocytosis/drug effects , Exocytosis/radiation effects , Hydrogen-Ion Concentration , Kinetics , Light , Membrane Fusion , Mice , Neurons/drug effects , Neurons/metabolism , Neurons/radiation effects , PC12 Cells , Protein Structure, Tertiary , RNA Interference , Rats , Recombinant Fusion Proteins/metabolism , Secretory Vesicles/drug effects , Secretory Vesicles/metabolism , Secretory Vesicles/radiation effects , Synaptic Potentials , Synaptic Transmission/drug effects , Synaptic Transmission/radiation effects , Synaptic Vesicles/drug effects , Synaptic Vesicles/metabolism , Synaptic Vesicles/radiation effects , Transfection , Vacuolar Proton-Translocating ATPases/genetics
2.
Neuropharmacology ; 74: 23-31, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23537500

ABSTRACT

NMDA receptors have been known to play a central role in long-term potentiation at glutamatergic synapses in principal cells for thirty years. In contrast, their roles in the development and activity-dependent plasticity of synapses in inhibitory circuits have only recently begun to be understood. Progress has, to a great extent, been hampered by the extensive diversity of GABAergic cell types in the CNS. However, anatomical, immunohistochemical and electrophysiological methods have allowed distinct types to be identified, with the result that consistent patterns of synaptic plasticity have begun to emerge. This review summarizes recent evidence on the role of NMDA receptors in the development and plasticity of GABAergic synapses on principal cells and of glutamatergic synapses on identified interneurons. A major challenge is to understand how NMDA receptors affect the routing of information in healthy inhibitory circuits, and how changes in NMDA receptor function may contribute to altered circuit function in disorders such as schizophrenia. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.


Subject(s)
GABAergic Neurons/physiology , Neural Inhibition/physiology , Neuronal Plasticity/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Brain/metabolism , Brain/physiology , Brain/physiopathology , Glutamic Acid/physiology , Humans , Interneurons/metabolism , Interneurons/physiology , Models, Neurological , Receptors, N-Methyl-D-Aspartate/metabolism , Schizophrenia/physiopathology , Synaptic Transmission/physiology
3.
Neuron ; 75(6): 951-62, 2012 Sep 20.
Article in English | MEDLINE | ID: mdl-22998865

ABSTRACT

Until recently, the study of plasticity of neural circuits focused almost exclusively on potentiation and depression at excitatory synapses on principal cells. Other elements in the neural circuitry, such as inhibitory synapses on principal cells and the synapses recruiting interneurons, were assumed to be relatively inflexible, as befits a role of inhibition in maintaining stable levels and accurate timing of neuronal activity. It is now evident that inhibition is highly plastic, with multiple underlying cellular mechanisms. This Review considers these recent developments, focusing mainly on functional and structural changes in GABAergic inhibition of principal cells and long-term plasticity of glutamateric recruitment of inhibitory interneurons in the mammalian forebrain. A major challenge is to identify the adaptive roles of these different forms of plasticity, taking into account the roles of inhibition in the regulation of excitability, generation of population oscillations, and precise timing of neuronal firing.


Subject(s)
GABAergic Neurons/physiology , Nerve Net/physiology , Neural Inhibition/physiology , Neuronal Plasticity , Animals , Models, Biological , Nerve Net/cytology
4.
Neuron ; 75(3): 451-66, 2012 Aug 09.
Article in English | MEDLINE | ID: mdl-22884329

ABSTRACT

Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns.


Subject(s)
Neocortex/metabolism , Neural Pathways/metabolism , Neuronal Plasticity/physiology , Neurons/metabolism , Presynaptic Terminals/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Computer Simulation , Excitatory Postsynaptic Potentials/physiology , Mice , Mice, Transgenic , Microscopy, Confocal , Neocortex/cytology , Neurons/cytology , Patch-Clamp Techniques , Synaptic Transmission/physiology
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