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Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor alpha (TNFalpha), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNFalpha has the opposite effects. Thus, the continual presence of TNFalpha is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNFalpha may play roles in synaptic plasticity and modulating responses to neural injury.
Glia, long considered to be primarily supportive of neurons, are now thought to be more active participants in neural circuit function (1, 2). Recently, it has been shown that astrocytes are required for normal synaptogenesis and synaptic stability due to the release of diffusible, extracellular signals) (3-- 5), one of which appears to be cholesterol (6). Whether glia are required for the rapid continual maintenance of synaptic strength is unknown. Here we present evidence that in both cultured hippocampal neurons and hippocampal slices, glial cells constitutively release the cytokine TNFalpha, which markedly influences synaptic strength at excitatory synapses via rapid effects on the trafficking of AMPA (alpha-- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors (AMPARs). That TNFalpha might influence surface expression of AMPARs and synaptic strength was suggested by observations that TNFa enhanced brainstem neuron responses to excitatory afferent inputs (7) and potentiated the cell death induced by injection of the excitotoxin kainate into the spinal cord, an effect that was blocked by an AMPAR antagonist (8). Furthermore, several reports have suggested that TNFalpha may influence synaptic function (9-11).
These results provide support for a novel role for glia in the rapid control of synaptic strength at excitatory synapses, as well as identify a protein, TNFalpha, that is necessary for fulfilling this function. The close apposition of astrocytes with excitatory synapses (27) provides a clear morphological substrate for facilitating this glial-neuronal communication. Our findings suggest possible novel roles for glial-released TNFalpha in normal and pathological brain function. For example, if neural activity influences TNFalpha production, this may contribute to the changes in synaptic strength that occur during various forms...