Long-term potentiation (LTP) of the excitatory synapses of the perforant path onto the granule cells of the fascia dentata was prevented, or greatly reduced in amount, by stimulation of the contralateral hilus, a source of the commissural afferents and an indirect source of granule cell inhibition. The LTP was reduced only when the onset of contralateral stimulation fell within 50 ms before and 1 ms after the onset of the perforant path conditioning train. Over this time interval, the ability of the volley from the contralateral hilus to block granule cell discharge (population spike) caused by the perforant path conditioning train varied, but not with a time course corresponding to the reduction of LTP. Although trains of impulses applied at high frequency (3-8 pulses at 400 Hz) were often able to block the perforant path LTP completely, single shocks strong enough to block the perforant path population spike were not sufficient to reduce LTP. The results support Marr's proposal that local inhibitory networks may set the threshold for producing long-term synaptic modification. They do not support Hebb's nor Uttley's proposal since the long-term synaptic modification did not depend on either the occurrence or the absence of a postsynaptic action potential.U