Drug Action
drug action
The 15th David Smith Lecture in Anatomical Neuropharmacology: Professor Tim Bliss, "Memories of long term potentiation
The David Smith Lectures in Anatomical Neuropharmacology, Part of the 'Pharmacology, Anatomical Neuropharmacology and Drug Discovery Seminars Series', Department of Pharmacology, University of Oxford. The 15th David Smith Award Lecture in Anatomical Neuropharmacology will be delivered by Professor Tim Bliss, Visiting Professor at UCL and the Frontier Institutes of Science and Technology, Xi’an Jiaotong University, China, and is hosted by Professor Nigel Emptage. This award lecture was set up to celebrate the vision of Professor A David Smith, namely, that explanations of the action of drugs on the brain requires the definition of neuronal circuits, the location and interactions of molecules. Tim Bliss gained his PhD at McGill University in Canada. He joined the MRC National Institute for Medical Research in Mill Hill, London in 1967, where he remained throughout his career. His work with Terje Lømo in the late 1960’s established the phenomenon of long-term potentiation (LTP) as the dominant synaptic model of how the mammalian brain stores memories. He was elected as a Fellow of the Royal Society in 1994 and is a founding fellow of the Academy of Medical Sciences. He shared the Bristol Myers Squibb award for Neuroscience with Eric Kandel in 1991, the Ipsen Prize for Neural Plasticity with Richard Morris and Yadin Dudai in 2013. In May 2012 he gave the annual Croonian Lecture at the Royal Society on ‘The Mechanics of Memory’. In 2016 Tim, with Graham Collingridge and Richard Morris shared the Brain Prize, one of the world's most coveted science prizes. Abstract: In 1966 there appeared in Acta Physiologica Scandinavica an abstract of a talk given by Terje Lømo, a PhD student in Per Andersen’s laboratory at the University of Oslo. In it Lømo described the long-lasting potentiation of synaptic responses in the dentate gyrus of the anaesthetised rabbit that followed repeated episodes of 10-20Hz stimulation of the perforant path. Thus, heralded and almost entirely unnoticed, one of the most consequential discoveries of 20th century neuroscience was ushered into the world. Two years later I arrived in Oslo as a visiting post-doc from the National Institute for Medical Research in Mill Hill, London. In this talk I recall the events that led us to embark on a systematic reinvestigation of the phenomenon now known as long-term potentiation (LTP) and will then go on to describe the discoveries and controversies that enlivened the early decades of research into synaptic plasticity in the mammalian brain. I will end with an observer’s view of the current state of research in the field, and what we might expect from it in the future.
Neuronal plasticity and neurotrophin signaling as the common mechanism for antidepressant effect
Neuronal plasticity has for a long time been considered important for the recovery from depression and for the antidepressant drug action, but how the drug action is translated to plasticity has remained unclear. Brain-derived neurotrophic factor (BDNF) and its receptor TRKB are critical regulators of neuronal plasticity and have been implicated in the antidepressant action. We have recently found that many, if not all, different antidepressants, including serotonin selective SSRIs, tricyclic as well as fast-acting ketamine, directly bind to TRKB, thereby promoting TRKB translocation to synaptic membranes, which increases BDNF signaling. We have previously shown that antidepressant treatment induces a juvenile-like state of activity in the cortex that facilitates beneficial rewiring of abnormal networks. We recently showed that activation of TRKB receptors in parvalbumin-containing interneurons orchestrates cortical activation states and is both necessary and sufficient for the antidepressantinduced cortical plasticity. Our findings open a new framework how the action of antidepressants act: rather than regulating brain monoamine concentrations, antidepressants directly bind to TRKB and allosterically promote BDNF signaling, thereby inducing a state of plasticity that allows re-wiring of abnormal networks for better functionality.