Interaction of calcineurin and type-A GABA receptor gamma 2 subunits produces long-term depression at CA1 inhibitory synapses.
Long-term depression (LTD) is an activity-dependent weakening of synaptic efficacy at individual inhibitory synapses, a possible cellular model of learning and memory. Here, we show that the induction of LTD of inhibitory transmission recruits activated calcineurin (CaN) to dephosphorylate type-A GABA receptor (GABA(A)Rs) via the direct binding of CaN catalytic domain to the second intracellular domain of the GABA(A)R-gamma(2) subunits. Prevention of the CaN-GABA(A) receptor complex formation by expression of an autoinhibitory domain of CaN in the hippocampus of transgenic mice blocks the induction of LTD. Conversely, genetic expression of the CaN catalytic domain in the hippocampus depresses inhibitory synaptic responses, occluding LTD. Thus, an activity-dependent physical and functional interaction between CaN and GABA(A) receptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses.
Wang
Jian
J
Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Canada, T2N 4N1.
Liu
ShuHong
S
Haditsch
Ursula
U
Tu
WeiHong
W
Cochrane
Kimberley
K
Ahmadian
Gholamreza
G
Tran
Linda
L
Paw
Jadine
J
Wang
YuTian
Y
Mansuy
Isabelle
I
Salter
Michael M
MM
Lu
You Ming
YM
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D004558:Electric Stimulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D046911:Macromolecular Substances; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*
C546280:Gabrg2 protein, mouse; D046911:Macromolecular Substances; D021122:Protein Subunits; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D019703:Calcineurin