The effects of botulinum A neurotoxin and tetanus toxin were studied in cultured mouse spinal cord neurons. In approximately 60% of the neurons (n = 150), botulinum A neurotoxin caused paroxysmal depolarizing events. In two cells hyperpolarizing shifts were observed. The pattern of the burst-like activity varied in shape and frequency in individual cells. Between the paroxysmal events, ongoing synaptic activity could be recorded. The other 40% of the treated neurons did not develop a characteristic pattern of bursts, but there was a decrease in frequency of synaptically generated events. In contrast to botulinum A neurotoxin, tetanus toxin invariably produced well organized paroxysmal events without any synaptic activity between them. At later stages botulinum A neurotoxin and tetanus toxin blocked inhibitory and excitatory postsynaptic potentials in all neurons studied. These results have demonstrated, for the first time using electrophysiological techniques, that botulinum A neurotoxin blocks both excitatory and inhibitory synaptic transmission in the mammalian central nervous system. There are however differences between these effects of botulinum A neurotoxin and the actions of tetanus toxin on these cells. It is suggested that at the femtomolar range tetanus toxin blocks selectively central inhibitory systems and botulinum A neurotoxin the motor endplate. At the picomolar range both toxins affect many if not all, transmitter systems.