Homosynaptic Long-Term Depression in Area CA1 of Hippocampus and Effects ofN-Methyl-D-Aspartate Receptor Blockade

Abstract

We tested a theoretical prediction that patterns ofexcitatory input activity that consistently fail to activate target neurons sufficiently to induce synaptic potentiation will instead cause a specific synaptic depression. To realize this situation experimentally, the Schaffer collateral projection to area CAl in rat hippocampal slices was stimulated electrically at frequencies ranging from 0.5 to 50 Hz. Nine hundred pulses at 1-3 Hz consistently yielded a depression of the CAl population excitatory postsynaptic potential that persisted without signs of recovery for >1 hr after cessation of the conditioning stimulation. This long-term depression was specific to the conditioned input, ruling out generalized changes in postsynaptic responsiveness or excitability. Three lines of evidence suggest that this effect is accounted for by a modification of synaptic effectiveness rather than damage to or fatigue of the stimulated inputs. First, the effect was dependent on the stimulation frequency; 900 pulses at 10 Hz caused no lasting change, and at 50 Hz a synaptic potentiation was usually observed. Second, the depressed synapses continued to support long-term potentiation in response to a high-frequency tetanus.Third, the effects of conditioning stimulation could be prevented by application of NMDA receptor antagonists. Thus, our data suggest that synaptic depression can be triggered by prolonged NMDA receptor activation that is below the threshold for inducing synaptic potentiation. We propose that this mechanism is important for the modifications of hippocampal response properties that underlie some forms of learning and memory.A cardinal feature of neuronal responses in the central nervous system is stimulus selectivity. Work on a number of preparations, including the developing visual cortex (1), adult somatosensory cortex (2), and hippocampus (3), has shown convincingly that neuronal selectivity can be modified by experience. It is a widely held belief that such modifications are a likely basis for learning and memory in mammals.Experience-dependent shifts in selectivity require that neurons acquire responsiveness to new stimuli and lose responsiveness to previously effective stimuli. A critical question concerns the mechanisms whereby this is accomplished. According to a theory developed for visual cortex (4-6), stimulus selectivity will evolve if excitatory synaptic inputs are potentiated when they consistently yield postsynaptic responses greater than a critical value (called the modification threshold, Om) and are depressed when they consistently yield responses greater than zero (the average "spontaneous" value) but less than 0m. Because the value of the modification threshold is a function of the average postsynaptic cell activity (5, 6), the selectivity ofa neuron can be modified when the probability of different patterns ofinput activity shifts, as it would when the animal is experiencing a novel environment.On the basis of work done on long-term potentiation (LTP) in area CA1 of the hippocampus (7)...