EXCITATORY STIMULATION DURING POSTSYNAPTIC INHIBITION INDUCES LONG-TERM DEPRESSION IN HIPPOCAMPUS IN-VIVO

1. As part of an effort to evaluate the biological plausibility of theoretically derived principles of synaptic modification, we studied activity-dependent long-term depression (LTD) of glutamatergic transmission in the hippocampus of anesthetized adult rats. Field potentials of CA1 pyramidal cells evoked by single-pulse stimulation (0.1 Hz) of the commissural afferents were recorded before and after paired-pulse stimulation (0.5 Hz) of the same pathway. A train of 150 or 200 paired pulses produced robust LTD of the commissural input to the CA1 pyramidal neurons when the interstimulus interval (ISI) of the pairs was short (25 ms) but not when the ISI was long (1,000 ms). 2. Paired-pulse stimulation with the short but not with the long ISI also was associated with pronounced inhibition of pyramidal cell firing upon the second pulse of a pair, despite the fact that the excitatory input was facilitated with the short-ISI paradigm. The inhibition of pyramidal cell activity was mediated by input to the pyramidal cells from local gamma-aminobutyric acid (GABA)-releasing interneurons activated by commissural fibers and/or CA1 recurrent collaterals, because the inhibition was eliminated by local administration of the selective GABA(A) receptor antagonist, bicuculline (50 mu M), near the recording site. 3. Postsynaptic input from GABAergic interneurons was necessary for the induction of LTD, because short-ISI paired-pulse stimulation failed to produce LTD in the presence of bicuculline. 4. N-methyl-D-aspartate (NMDA) receptor-mediated excitation also was necessary for the induction of LTD, because administration of the selective NMDA receptor antagonist, D-2-amino-5-phosphonvaleric acid (100 mu M), near the recording site prevented the development of LTD. The failure to induce LTD was not due to loss of input by GABAergic interneurons, because APV did not abolish paired-pulse inhibition. 5. Our findings demonstrate for the first time in the hippocampus in vivo the induction of LTD by patterned stimulation of the afferent pathway. Furthermore, they establish that GABAergic interneurons play an essential role in use-dependent reduction of excitatory synaptic transmission, and identify a mechanism which justifies the implemention in artificial neural networks of learning rules that incorporate activity-dependent decreases of connection weights.