Coordinated signalling between presynaptic terminals and their postsynaptic targets is essential for the development and function of central synapses. In addition to diffusible molecules, this bidirectional flow of information could involve direct interactions through cell-adhesion molecules. Here, we show that one class of cell-adhesion molecule, the integrins, are required for the functional maturation of hippocampal synapses in vitro. At immature synapses, a high probability of glutamate release (Pr) was correlated with the expression of postsynaptic NMDA (N-methyl-D-aspartate) receptors containing the NR2B subunit. The activity-dependent reduction in Pr and a switch in the subunit composition of synaptic NMDA receptors was prevented by chronic blockade with peptides containing the integrin-binding site Arg-Gly-Asp (RGD), or by a functional antibody against the beta3 integrin subunit. Active synapses, monitored by the uptake of antibodies against the intraluminal domain of synaptotagmin I, also had beta3 subunit immunoreactivity. Our results provide evidence that integrin-mediated signalling is essential for the orchestrated maturation of central excitatory synapses.

In skeletal muscle, L-type Ca2+ channels act as voltage sensors to control ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum. It has recently been demonstrated that these ryanodine receptors generate a retrograde signal that modifies L-type Ca2+ -channel activity. Here we demonstrate a tight functional coupling between ryanodine receptors and L-type Ca2+ channel in neurons. In cerebellar granule cells, activation of the type-1 metabotropic glutamate receptor (mGluR1) induced a large, oscillating increase of the L-type Ba2+ current. Activation occurred independently of inositol 1,4,5-trisphosphate and classical protein kinases, but was mimicked by caffeine and blocked by ryanodine. The kinetics of this blockade were dependent on the frequency of Ba2+ current stimulation. Both mGluR1 and caffeine-induced increase in L-type Ca2+ -channel activity persisted in inside-out membrane patches. In these excised patches, ryanodine suppressed both the mGluR1- and caffeine-activated L-type Ca2+ channels. These results demonstrate a novel mechanism for Ca2+ -channel modulation in neurons.