Diffusible Messengers and Intercellular Signaling: Locally Distributed Synaptic Potentiation in the Hippocampus

Abstract

Diffusible messengers like nitric oxide (NO) have been proposed to act as intercellular signals in the production of long term potentiation (LTP; for review, see Schuman and Madison 1993). The postsynaptic generation of such a diffusible messenger leads to the prediction that synapses in the vicinity of the messenger-producing synapse will also be influenced. We have tested this prediction directly by recording simultaneously from two postsynaptic CA1 neurons and recording synaptic strength in response to Schaffer collateral stimulation before and after LTP induction (by pairing 1 Hz stimulation with postsynaptic depolarization) in one neuron (see also Bonhoefer et al. 1989). In experiments where we impaled two pyramidal neurons in close proximity (132.9 ± 39.6 μM intersomatic distance, ISD), the paired cell exhibited robust LTP (186.0 ± 15.6 mean percentage of baseline) and the nearby neighboring neuron also exhibited a significant increase in synaptic strength (130.6 ± 9.5%; n=19). Postsynaptic injection of the NO synthase inhibitor L-Me-Arg into the paired cell blocked LTP production in that cell (95.8 +/− 6.9%) as well as in the nearby cell (102.2 ± 10.1%; ISD = 143.3 ± 43.6 μM; n=18). This spreading of potentiation was spatially restricted as it was not observed when the neighboring cell was > 500 μM away (paired cell LTP, 170.1 ± 11.8%; distant neighbor, 97.6 ± 0.7%; ISD = 674.0 ± 38.3 μM; n=15). Since previous findings showed that LTP can be blocked by various postsynaptic manipulations, we were interested in whether these processes are also important in the neighboring cell. We found that a combination of dialysis, Ca²⁺ chelators, and membrane hyperpolarization in the nearby neighboring cell blocked the spreading of enhancement usually observed (paired 195.7 ± 43.1; neighbor, 105.6 ± 24.7; n=8). These results suggest that the neighboring cell may play an active role in the enhancement described, either as a target site for a diffusible signal, or perhaps for the generation of an additional messenger(s).