Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-D-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca 2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca 2+ channels. Intracellular infusion of NMDARs or Ca
2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocytedependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites.synapse heterogeneity | synaptic strength | astrocyte | hippocampal neuron | heterosynaptic plasticity A n enduring challenge in neurobiology is to understand how neurons set the strengths of their numerous synapses to efficiently process and store different information while maintaining network homeostasis. Electrophysiology and imaging approaches have revealed that synapses display a high degree of functional heterogeneity, even for those sharing the same axon or dendrite (1-3). The observation that synaptic strengths are heterogeneous, in turn, suggests that synapses can operate independently from one another. Accordingly, many studies have demonstrated the input-specificity of Hebbian and also of homeostatic forms of synaptic plasticity, where synaptic changes are restricted to inputs whose activity is altered (4-6). Nevertheless, such a synapse-autonomous behavior could potentially compromise the global network homeostasis by biasing the overall activity toward excitation or depression, and to overcome this issue, it has been proposed that distinct inputs cooperate by coordinating their relative strengths through heterosynaptic interactions (7-9). In support of the idea that synapses behave as interdependent rather than isolated functional units, the restriction of synaptic strength changes to active inputs has been demonstrated to break down at times, with the induction of synaptic plasticity in the stimulated input accompanying either synaptic depression or potentiation of the nonstimulated inputs (10-13). In a highly studied plasticity paradigm of long-term potentiation (LTP) at hippocampal Schaffer collateral-CA1 synapses, tetanic stimulation that induces LTP is often accompanied by presynaptic long-term depression (LTD) of nonstimulated Schaffer collat...