1. Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California 94304-5485, USA

Correspondence to: Robert C. Malenka¹ Correspondence and requests for materials should be addressed to R.C.M. (Email: malenka@stanford.edu).

Two general forms of synaptic plasticity that operate on different timescales are thought to contribute to the activity-dependent refinement of neural circuitry during development: (1) long-term potentiation (LTP) and long-term depression (LTD), which involve rapid adjustments in the strengths of individual synapses in response to specific patterns of correlated synaptic activity, and (2) homeostatic synaptic scaling, which entails uniform adjustments in the strength of all synapses on a cell in response to prolonged changes in the cell's electrical activity^{1, 2}. Without homeostatic synaptic scaling, neural networks can become unstable and perform suboptimally^{1, 2, 3}. Although much is known about the mechanisms underlying LTP and LTD⁴, little is known about the mechanisms responsible for synaptic scaling except that such scaling is due, at least in part, to alterations in receptor content at synapses^{5, 6, 7}. Here we show that synaptic scaling in response to prolonged blockade of activity is mediated by the pro-inflammatory cytokine tumour-necrosis factor- (TNF-). Using mixtures of wild-type and TNF--deficient neurons and glia, we also show that glia are the source of the TNF- that is required for this form of synaptic scaling. We suggest that by modulating TNF- levels, glia actively participate in the homeostatic activity-dependent regulation of synaptic connectivity.

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