Low-frequency stimulation at the troughs of theta-oscillation induces long-term depression of previously potentiated CA1 synapses.

1. The induction of long-term weakening of synaptic transmission in rat hippocampal slices was examined in CA1 synapses during cholinergic modulation. 2. Bath application of the cholinergic agonist carbachol (50 microM) activated an oscillation of the local field potential in the theta-frequency range (5-12 Hz), termed theta. It was previously shown that a stimulation train of 40 single shocks (at 0.1 Hz) to the Schaffer collateral-commisural afferents, each synchronized with positive peaks of theta, caused homosynaptic long-term enhancement in CA1. Furthermore, long-term depression (LTD) was sporadically observed when the stimulation train was given at negative troughs of theta. Here we have sought to determine stable conditions for LTD induction during theta. 3. Synaptic weakening was reliably obtained, by giving 40 shocks (at 0.1 Hz) at theta-troughs, only in pathways that had been previously potentiated. This decrement, termed theta-LTD, was synapse specific because it did not occur in an independent pathway not stimulated during theta. The interval between the initial potentiating tetanus and theta-LTD induction could be as long as 90 min. 4. theta-LTD could be saturated; after consecutive episodes of theta-LTD induction, no significant further depression was obtained. Moreover, theta-LTD could be reversed by tetanic stimulation. 5. theta-LTD could prevent the induction of LTD by 600-900 pulses at 1 Hz. This suggests that the two protocols may share common mechanisms at the synaptic level. 6. We conclude that single presynaptic spikes that occur at low frequency and are properly timed to the troughs of theta may be a relevant mechanism for decreasing the strength of potentiated synapses.