Tumor necrosis factor-alpha (TNF-alpha) is a cytokine secreted by activated astrocytes and is known to alter evoked synaptic activity in slices of adult rat hippocampus. In this paper we show that TNF-alpha increases the frequency of spontaneous miniature synaptic currents in cultured hippocampal neurons, acting at nanomolar concentrations. In addition, we show that the mRNA for the 55 kDa TNF-alpha receptor (TNF-R1) is detected in embryonic rat hippocampal cultures, as well as in acutely dissected embryonic and adult rat hippocampi. Possible transduction pathways mediating the TNF-alpha effect are discussed.