Calcium stores regulate the polarity and input specificity of synaptic modfication

Activity-induced synaptic modification is essential for the development and plasticity of the nervous system(1-3). 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 depression(2,3) (LTP or LTD). An important unresolved issue is whether and to what extent LTP and LTD are restricted to the activated synapses(4-8). 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 (InsP(3)) receptors, respectively. Functional blockade or genetic deletion of type 1 InsP(3) 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 InsP(3) receptors, regulates both the polarity and input specificity of activity-induced synaptic modification.