An introduction to a symposium dedicated to the scientific achievements of Roger Nicoll

This special symposium issue contains articles based on talks given at a recent 2 day symposium in honour of Roger A Nicoll, Professor in the Department of Cellular and Molecular Pharmacology at the University of California, San Francisco (UCSF). Roger initially trained in medicine but became interested in neuroscience as a result of reading the work of Sir John Eccles. From 1973 to 1975, he worked with Eccles in Buffalo, New York, and then took a faculty position at UCSF in 1975. Here he initially studied synaptic transmission in the olfactory bulb (Jahr & Nicoll, 1982) and hippocampal formation (Alger & Nicoll, 1982) but soon moved almost exclusively to the hippocampus where his laboratory has been studying the neurons and their synaptic connections for the last 30 years. These studies have examined the properties of both excitatory and inhibitory systems and led to fundamental changes in our understanding of both forms of synaptic transmission. His laboratory has been at the forefront of understanding the cellular and biochemical mechanisms that underpin synaptic plasticity, particularly long-term potentiation. He has trained dozens of scientists, many of whom are now are senior lab heads spread over the world. This symposium was a celebration of Roger's life in science, bringing together people who have been in his laboratory as well as his closest colleagues to discuss their areas within the lab as well as areas of their own current research. It was a wonderful event with Professor Eric Kandel giving the keynote address.

During Roger's career at UCSF, he has worked on various aspects of synaptic transmission in the hippocampus mostly working on area CA1 but also on CA3. Much of the initial focus was on inhibitory transmission at GABAergic synapses on CA1 pyramidal neurons. These early studies suggested that the chloride gradient in adult pyramidal neurons was not the same throughout the neuron but that GABA in fact has excitatory actions in the dendritic tree as compared with the soma (Alger & Nicoll, 1982). The reason for the depolarising action of GABA remains poorly understood with some suggestions of HCO₃⁻ permeability. Even with the molecular identification of the chloride transporters the reason for an altered chloride gradient remains unclear.

GABA had been known to activate two types of receptors, GABA_A and GABA_B, for many years. One of the key findings was the demonstration that GABA_B receptors are coupled to G-proteins and activate inwardly rectifying potassium channels. This action was shown to underlie the slow GABAergic IPSC in hippocampal neurons and remains the benchmark in this area (Dutar & Nicoll, 1988).

GABAergic synapses had been known to undergo a form of synaptic plasticity known as depolarization-induced suppression of inhibition (DSI; Pitler & Alger, 1994). This form of inhibition has been studied over several years and was known to require a rise in postsynaptic calcium though the mechanisms of its induction remained obscure. In 2002 the Nicoll laboratory showed that DSI was mediated by the release of an endocannabinoid as a result of the rise in postsynaptic calcium (Wilson & Nicoll, 2002). The released endocannabinoid acted on GABAergic terminals to activate CB1 receptors and reduce transmitter release. This finding has spawned an entire area of work that has led to a new understanding of the action of cannabinoids in the mammalian CNS. The findings in this area are summarised by Brad Alger, one of the original discoverers of DSI.

In the mid to late 1980s, Roger turned his attention to glutamatergic synapses, initially focusing on the physiology of these synapses and the mechanisms that underlie the induction and maintenance of LTP (Kauer et al. 1988). These studies focused on the Schaffer collateral synapses on CA1 pyramidal neurons as well as mossy fibre synapses on CA3 pyramidal neurons (Zalutsky, 1990). This work led to the determination of key properties of synaptic plasticity. In both systems, there was a heady dispute both as to the locus of induction as well as the site of change that maintained the plasticity (Malenka & Nicoll, 1999). Curiously, while many feel that these issues have been settled, this dispute continues to this day. Dimitri Kullman, who was involved in the early days of this story provides a summary of the key issues in the ‘LTP wars’ and his view of where the state of play is now.

In studying the underlying mechanisms of LTP, a large part of the focus of the Nicoll group has been on postsynaptic mechanisms. This focus shifted to understanding the mechanisms involved in maintaining neurotransmitter receptors and their partners at the postsynaptic membrane. These studies, along with several other laboratories, have shifted the focus to the identification of chaperones for glutamate receptors (Nicoll et al. 2006) and mechanisms of receptor trafficking during development, maintenance and plasticity of glutamatergic synapses. Susumu Tomita and Pablo Castillo provide a summary of the state of the field with respect to one type of ionotropic receptor – the kainate receptors.

These three reviews provide insights into three distinct areas of research contributions of Roger Nicoll over the last 20 years. The symposium was a great success and provided the opportunity to meet many old friends and colleagues to catch up and exchange new ideas. More than one speaker commented on looking forward to the contributions Roger is likely to produce during the next decade.