GABA promotes the competitive selection of dendritic spines by controlling local Ca2+ signaling


Activity-dependent competition of synapses plays a key role in neural organization and is often promoted by GABA; however, its cellular bases are poorly understood. Excitatory synapses of cortical pyramidal neurons are formed on small protrusions known as dendritic spines, which exhibit structural plasticity. We used two-color uncaging of glutamate and GABA in rat hippocampal CA1 pyramidal neurons and found that spine shrinkage and elimination were markedly promoted by the activation of GABAA receptors shortly before action potentials. GABAergic inhibition suppressed bulk increases in cytosolic Ca2+ concentrations, whereas it preserved the Ca2+ nanodomains generated by NMDA-type receptors, both of which were necessary for spine shrinkage. Unlike spine enlargement, spine shrinkage spread to neighboring spines (<15 μm) and competed with their enlargement, and this process involved the actin-depolymerizing factor ADF/cofilin. Thus, GABAergic inhibition directly suppresses local dendritic Ca2+ transients and strongly promotes the competitive selection of dendritic spines.

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Figure 1: Spine shrinkage and elimination induced with the spike-timing protocol.
Figure 2: Spine shrinkage spread and GABA effects.
Figure 3: Pharmacology of spine shrinkage.
Figure 4: Competition of the enlargement and shrinkage of neighboring spines.
Figure 5: The spatial profile of GABA uncaging-mediated inhibition of bAP-induced dendritic Ca2+ transients.
Figure 6: Spine Ca2+ signaling and effects of cytosolic EGTA.
Figure 7: Spine Ca2+ signaling and effects of cytosolic BAPTA.


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We thank K. Mizuno, K. Ohashi, G.J. Augustine, C. O'Donnell, S. Okabe and J. Eilers for discussions and C. Maeda, M. Ogasawara, H. Ohno, M. Ishikawa and K. Tamura for technical assistance. This work was supported by Grants-in-Aid for Specially Promoted Area (no. 21000009 to H.K.), Scientific Research (C) (no. 21500367 to J.N.), Scientific Research on Priority Areas ('Elucidation of neural network function in the brain', no. 20021008 to M.M.), Young Scientist (A) (no. 19680020 to M.M.), Scientific Research on Innovative Areas 'Mesoscopic Neurocircuitry' (no. 22115005 to M.M.), the Global COE Program ('Integrative Life Science based on the study of Biosignaling Mechanisms' to H.K.) and the Strategic Research Program for Brain Sciences ('Neuroinformatics of Emotion' to H.K.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by the US National Institutes of Health (grants GM53395 and NS69720 to G.C.R.E.-D.). In addition, this work was supported by a Mitsubishi Foundation grant to M.M. and a Research Grant from the Human Frontier Science Program to H.K.

Author information

T.H., J.N. and H.K. conceived the experiments. T.H., J.N., M.M. and S.W. performed the slice experiments. A.H. and N.T. contributed to the molecular experiments. G.C.R.E.-D. synthesized the caged glutamate compound. H.K., J.N., T.H. and G.C.R.E.-D. wrote the paper.

Correspondence to Haruo Kasai.

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G.C.R.E.-D. has filed a preliminary patent declaration in the USA for the synthesis of dinitroindolinyl-caged neurotransmitters.

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Hayama, T., Noguchi, J., Watanabe, S. et al. GABA promotes the competitive selection of dendritic spines by controlling local Ca2+ signaling. Nat Neurosci 16, 1409–1416 (2013) doi:10.1038/nn.3496

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