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 the oretically derived principles of synaptic modification, we studied act ivity-dependent long-term depression (LTD) of glutamatergic transmissi on 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 sti mulation (0.5 Hz) of the same pathway. A train of 150 or 200 paired pu lses 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 stim ulation with the short but not with the long ISI also was associated w ith pronounced inhibition of pyramidal cell firing upon the second pul se of a pair, despite the fact that the excitatory input was facilitat ed with the short-ISI paradigm. The inhibition of pyramidal cell activ ity was mediated by input to the pyramidal cells from local gamma-amin obutyric acid (GABA)-releasing interneurons activated by commissural f ibers and/or CA1 recurrent collaterals, because the inhibition was eli minated by local administration of the selective GABA(A) receptor anta gonist, bicuculline (50 mu M), near the recording site. 3. Postsynapti c 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) recept or-mediated excitation also was necessary for the induction of LTD, be cause administration of the selective NMDA receptor antagonist, D-2-am ino-5-phosphonvaleric acid (100 mu M), near the recording site prevent ed the development of LTD. The failure to induce LTD was not due to lo ss of input by GABAergic interneurons, because APV did not abolish pai red-pulse inhibition. 5. Our findings demonstrate for the first time i n the hippocampus in vivo the induction of LTD by patterned stimulatio n of the afferent pathway. Furthermore, they establish that GABAergic interneurons play an essential role in use-dependent reduction of exci tatory 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.