Modulation of GABAergic transmission by activity via postsynaptic Ca2+-dependent regulation of KCC2 function.
Activity-induced modification of GABAergic transmission contributes to the plasticity of neural circuits. In the present work we found that prolonged postsynaptic spiking of hippocampal neurons led to a shift in the reversal potential of GABA-induced Cl- currents (E(Cl)) toward positive levels in a duration- and frequency-dependent manner. This effect was abolished by blocking cytosolic Ca2+ elevation and mimicked by releasing Ca2+ from internal stores. Activity- and Ca2+-induced E(Cl) shifts were larger in mature neurons, which express the K-Cl cotransporter KCC2 at high levels, and inhibition of KCC2 occluded the shifts. Overexpression of KCC2 in young cultured neurons, which express lower levels of KCC2 and have a more positive E(Cl), resulted in hyperpolarized E(Cl) similar to that of mature cells. Importantly, these young KCC2-expressing neurons became responsive to neuronal spiking and Ca2+ elevation by showing positive E(Cl) shifts. Thus, repetitive postsynaptic spiking reduces the inhibitory action of GABA through a Ca2+-dependent downregulation of KCC2 function.
Fiumelli
Hubert
H
Division of Neurobiology, Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720, USA.
Cancedda
Laura
L
Poo
Mu-ming
MM
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D018118:Chloride Channels / Q000502:physiology; D004553:Electric Conductivity; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D007425:Intracellular Membranes / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009994:Osmolar Concentration; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D027981:Symporters / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*; D000096922:K Cl- Cotransporters
D002118:Calcium; D018118:Chloride Channels; D011493:Protein Kinase C; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters