Inhibitory control of local excitatory circuits in the guinea-pig hippocampus

1. Exposure to the gamma-aminobutyric acid antagonist, picrotoxin, causes the discharge of hippocampal pyramidal cells to become synchronized. Synaptic mechanisms underlying the development of synchrony were investigated by recording from pairs of cells in the CA3 region of guinea-pig hippocampal slices. 2. Picrotoxin suppressed unitary inhibitory synaptic events. It appeared not to affect monosynaptic excitatory connections. Picrotoxin revealed latent excitatory connections in seven out of twenty-one dual recordings from burst-firing cells. 3. Post-synaptic events revealed by picrotoxin were elicited rarely by single action potentials. They were evoked with mean latencies of at least 8 ms and with more than 30% failures of transmission by bursts of three or more action potentials. They were suppressed by increasing extracellular Ca2+. They were considered to be mediated by polysynaptic excitatory pathways. 4. Polysynaptic excitatory post-synaptic potentials (e.p.s.p.s) had a smooth rising phase with time-to-peak of 15-40 ms and a falling phase of similar duration. Their amplitude was 2-3 mV at membrane potentials close to -70 mV. This shape was similar to that of summed e.p.s.p.s evoked by a burst of three to six action potentials at monosynaptic connections between CA3 cells. 5. One cell could evoke excitatory synaptic events in more than one follower cell, suggesting that axon collaterals mediating recurrent excitation were divergent. More than one polysynaptic excitatory pathway could exist between two cells. 6. We examined the role of recurrent excitatory synapses in the development of synchrony. As inhibition was suppressed by picrotoxin, simultaneous excitatory synaptic events appeared in recordings from pairs of cells. They occurred rhythmically at intervals of 0.5-3 s and grew in amplitude with time. Synchronous neuronal discharges were observed when the threshold for action potential generation was exceeded. 7. Firing induced in one cell could sometimes evoke a sequence of post-synaptic events in another cell as inhibition was suppressed. Initially, no connection was detected. On adding picrotoxin, a polysynaptic e.p.s.p. was revealed and with time longer-latency components were recruited to the synaptic event. The amplitude of later components grew until firing threshold was reached. 8. We suggest that synchronous firing develops due to the loss of inhibitory control over the spread of firing between CA3 pyramidal cells via divergent, polysynaptic, recurrent excitatory pathways.