CLC-3 channels modulate excitatory synaptic transmission in hippocampal neurons.
It is well established that ligand-gated chloride flux across the plasma membrane modulates neuronal excitability. We find that a voltage-dependent Cl(-) conductance increases neuronal excitability in immature rodents as well, enhancing the time course of NMDA receptor-mediated miniature excitatory postsynaptic potentials (mEPSPs). This Cl(-) conductance is activated by CaMKII, is electrophysiologically identical to the CaMKII-activated CLC-3 conductance in nonneuronal cells, and is absent in clc-3(-/-) mice. Systematically decreasing [Cl(-)](i) to mimic postnatal [Cl(-)](i) regulation progressively decreases the amplitude and decay time constant of spontaneous mEPSPs. This Cl(-)-dependent change in synaptic strength is absent in clc-3(-/-) mice. Using surface biotinylation, immunohistochemistry, electron microscopy, and coimmunoprecipitation studies, we find that CLC-3 channels are localized on the plasma membrane, at postsynaptic sites, and in association with NMDA receptors. This is the first demonstration that a voltage-dependent chloride conductance modulates neuronal excitability. By increasing postsynaptic potentials in a Cl(-) dependent fashion, CLC-3 channels regulate neuronal excitability postsynaptically in immature neurons.
Wang
Xue Qing
XQ
Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
Deriy
Ludmila V
LV
Foss
Sarah
S
Huang
Ping
P
Lamb
Fred S
FS
Kaetzel
Marcia A
MA
Bindokas
Vytautas
V
Marks
Jeremy D
JD
Nelson
Deborah J
DJ
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism
D018118:Chloride Channels; D002712:Chlorides; C115376:ClC-3 channel; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases