Calcium stores regulate the polarity and input specificity of synaptic modification

Activity-induced synaptic modification is essential for the development and plasticity of the nervous system1,2,3. Repetitive correlated activation of pre- and postsynaptic neurons can

induce persistent enhancement or decrement of synaptic efficacy, commonly referred to as long-term potentiation or depression2,3(LTP or LTD). An important unresolved issue is whether and to

what extent LTP and LTD are restricted to the activated synapses4,5,6,7,8. Here we show that, in the CA1 region of the hippocampus, reduction of postsynaptic calcium influx by partial

blockade of NMDA (N-methyl-d-aspartate) receptors results in a conversion of LTP to LTD and a loss of input specificity normally associated with LTP, with LTD appearing at heterosynaptic

inputs. The induction of LTD at homo- and heterosynaptic sites requires functional ryanodine receptors and inositol triphosphate (InsP3) receptors, respectively. Functional blockade or

genetic deletion of type 1 InsP3 receptors led to a conversion of LTD to LTP and elimination of heterosynaptic LTD, whereas blocking ryanodine receptors eliminated only homosynaptic LTD.

Thus, postsynaptic Ca2+, deriving from Ca2+ influx and differential release of Ca2+ from internal stores through ryanodine and InsP3 receptors, regulates both the polarity and input

specificity of activity-induced synaptic modification.

We thank T. Michikawa for providing an antibody against InsP3R1; T. V. P. Bliss and R. C. Malenka for helpful discussions and suggestions; and N. Spitzer, J. R. Henley, D. Zacharias, A. F.

Schinder, S. Andersen and F. Engert for critical comments on the manuscript. This work was supported in part by a grant from USNIH.

Present address: Department of Biochemistry, New York University School of Medicine, 550 First Avenue, New York, New York, 10016, USA

Present address: Department of Molecular and Cell Biology, University of California, Berkeley, California, 94720, USA

Makoto Nishiyama and Kunio Kato: These authors contributed equally to this work.

Department of Biology, University of California at San Diego, La Jolla, 92093-0357, California, USA

Mikoshiba Calciosignal Net Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Corporation (JST), Tokyo, 113-0021, Japan

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