Neural activity can induce persistent strengthening or weakening of synapses, known as long-term potentiation (LTP) or long-term depression (LTD), respectively. As potential cellular mechanisms underlying learning and memory, LTP and LTD are generally regarded as synapse-specific ''imprints'' of activity, although there is evidence in vitro that LTP/LTD may spread to adjacent synapses. Here, we report that LTP and LTD induced in vivo at retinotectal synapses of Xenopus tadpoles undergo rapid long-range retrograde spread from the optic tectum to the retina, resulting in potentiation and depression of bipolar cell synapses on the dendrites of retinal ganglion cells, respectively. The retrograde spread of LTP and LTD required retrograde signaling initiated by brainderived neurotrophic factor and nitric oxide in the tectum, respectively. Such bidirectional adjustment of the strength of input synapses in accordance to that of output synapses may serve to coordinate developmental refinement and learning functions of neural circuits.neural development Í retrograde signaling Í synaptic plasticity Í retinal ganglion cell P ersistent modification of synaptic efficacy by neural activity represents a cellular mechanism underlying learning and memory functions of the brain (1, 2). Activity-induced long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are found in many regions of developing and mature nervous systems (3-5). Because LTP/LTD induction often requires correlated presynaptic and postsynaptic activation, it is generally assumed that these bidirectional modifications are synapse-specific, i.e., only those synapses experiencing correlated presynaptic and postsynaptic activities are modified (2). This notion of synapse specificity has been widely used in computational analysis of activity-dependent modification of neural circuits. Experimental studies have indeed demonstrated input specificity in the induction of LTP/LTD, when activated and unactivated synaptic inputs are well separated (6-8).However, many studies in the past two decades have suggested that this notion of input specificity needs to be modified. Induction of LTP in one pathway was found to be accompanied by heterosynaptic depression of other pathways (9). Transmitters released at activated synapses may also ''spill over'' and modify adjacent synaptic sites (10). By examining specifically the issue of input specificity, several in vitro studies have shown that LTP/LTD induced at one set of synapses on a neuron could spread laterally to nearby synapses (11-16). Most surprisingly, in random networks formed by dissociated hippocampal neurons in culture, there is a rapid retrograde spread of potentiation/ depression from the site of LTP/LTD induction to the synaptic inputs on the dendrite of the presynaptic neuron (17, 18). Such long-range presynaptic spread of retrograde signals accompanying LTP/LTD induction is also implicated by the findings of rapid global modifications of intrinsic excitability of the presynaptic neuron a...