The Quest for the Associative Device for Hebbian-Like LTP-The Accidental Participant

In 1985 Holger Wigström (now deceased) and I published a proposed scenario for the induction of hippocampal Hebbian-like LTP to explain its input specificity and cooperativity. In this scenario LTP is induced by calcium influx through voltage-dependent NMDA receptor channels co-localized with the glutamate receptor channels (non-NMDA) mediating the expression of LTP. This co-localization, we argued, explained the input specificity, and the voltage dependence of these NMDA receptor channels explained the cooperativity. It will be described how this scenario emerged from our finding of a greatly facilitated LTP induction following blockade of postsynaptic inhibition, from our observation of a dendritic, possibly regenerative, event correlated with successful LTP induction, and to our recognition that these events were the result of NMDA receptor activation. Our observation of a likely synaptic co-localization of these receptor channels with the non-NMDA receptor channels, with the former contributing to an EPSP component with a slower onset and much longer duration, will be described. Finally, I will describe how our scenario became validated by our experiments pairing such single EPSPs with depolarization induced by injected current pulses, temporally associated with the NMDA component. This essay will conclude with some take-home messages regarding the Hebbian-like LTP as learned from these experiments: this form of synaptic learning most likely only occurs during disinhibition, its longevity strongly depends on the induction strength from a few minutes and upwards, with a strong induction event it can operate as a one-shot potentiation, and its time window for association may remain several 100 ms. Lastly, Hebbian-like LTP likely evolved to associate input events rather than an input event and somatic spike activity.