Episode 09 | The Cellular Basis of Learning

Episode SummaryRight now, as you listen, something extraordinary is happening inside your head. At thousands of tiny junctions between your neurons, calcium ions are flooding through molecular gates, enzymes are switching on like dominoes, and new receptor proteins are being inserted into your neural membranes. By the time you finish this sentence, the physical structure of your brain will have changed. This is what learning looks like at the cellular level.In this episode, we travel to a laboratory in Oslo, Norway, where in 1966 a young researcher named Terje Lomo accidentally discovered that synaptic connections could be strengthened for hours or even days. Together with Tim Bliss from London, he published findings in 1973 that would become one of the most cited papers in neuroscience, though it was largely ignored for an entire decade.We then dive into the elegant molecular machinery behind this process: the NMDA receptor, nature's own coincidence detector, which acts as a biological AND gate requiring two simultaneous signals before it opens. We trace the cascade from calcium entry through the CaMKII "molecular switch" to the insertion of new AMPA receptors and, ultimately, the activation of genes that make learning permanent. Along the way, we discover how Richard Morris proved the link between this synaptic mechanism and actual learning behavior, and how a 2014 experiment literally switched a memory off and on using light.Key Topics CoveredThe gap in understanding before LTP: Hebb's theory without experimental proofPer Andersen's laboratory in Oslo and the hippocampal slice preparationTerje Lomo's accidental discovery of long lasting potentiation in 1966Tim Bliss's arrival in 1968 and the landmark 1973 publicationThe NMDA receptor as a coincidence detector (biological AND gate)The magnesium block and voltage dependent gatingThe molecular cascade: calcium, CaMKII, AMPA receptor traffickingEarly LTP (protein modification) versus late LTP (new gene expression)The synaptic tagging and capture hypothesis (Frey and Morris, 1997)The Morris water maze and the APV experiments linking LTP to learningGenetic proof: CA1 specific NMDA receptor knockout mice (Tsien et al., 1996)Engineering memories with optogenetics (Nabavi et al., 2014)LTD and spike timing dependent plasticity as complementary mechanismsThe astroengram discovery: astrocytes as potential memory storage partnersLTP at 50: the 2023 Royal Society retrospectiveResearchers MentionedTerje Lomo (1935-2025, University of Oslo): Co-discoverer of LTP, first observed the phenomenon in 1966Tim Bliss (Francis Crick Institute, London): Co-discoverer of LTP, Fellow of the Royal Society, Brain Prize 2016Per Andersen (1930-2020, University of Oslo): Laboratory head, pioneered hippocampal slice preparationGraham Collingridge (University of Bristol/Toronto): Proved NMDA receptors are required for LTP induction (1983), Brain Prize 2016Richard Morris (University of Edinburgh): Invented the water maze (1981), APV experiments (1986), Brain Prize 2016John Lisman (1944-2017, Brandeis University): Proposed the CaMKII molecular switch hypothesisRoberto Malinow (UC San Diego): AMPA receptor trafficking, optogenetic LTP/LTD manipulationRobert Malenka (Stanford): Molecular mechanisms of synaptic plasticitySadegh Nabavi (UC San Diego): Lead author of the 2014 memory engineering studyJoe Tsien and Susumu Tonegawa (MIT): CA1 specific NMDA receptor knockout experimentsUwe Frey (Leibniz Institute): Co-author of the synaptic tagging hypothesisHenry Markram (Max Planck Institute): Spike timing dependent plasticity discovery (1997)Guo-Qiang Bi and Mu-Ming Poo (UC San Diego): Definitive characterization of STDP timing windows (1998)Key Studies and SourcesBliss, T.V.P. and Lomo, T. (1973). "Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path." Journal of Physiology, 232(2), 331-356.Collingridge, G.L., Kehl, S.J., and McLennan, H. (1983). "Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus." Journal of Physiology, 334, 33-46.Morris, R.G.M., Anderson, E., Lynch, G.S., and Baudry, M. (1986). "Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5." Nature, 319, 774-776.Lisman, J. (1994). "The CaMKII hypothesis for the storage of synaptic memory." Trends in Neurosciences, 17(10), 406-412.Frey, U. and Morris, R.G.M. (1997). "Synaptic tagging and long-term potentiation." Nature, 385, 533-536.Malinow, R. and Malenka, R.C. (2002). "AMPA receptor trafficking and synaptic plasticity." Annual Review of Neuroscience, 25, 103-126.Nabavi, S. et al. (2014). "Engineering a memory with LTP and LTD." Nature, 511, 348-352.Abraham, W.C. et al. (2024). "Long-term potentiation: 50 years on." Philosophical Transactions of the Royal Society B, 379(1906).Key Numbers to Remember1966: Year Lomo first observed long lasting potentiation1973: Year the landmark Bliss and Lomo paper was published7 years: Gap between the initial observation and publication83%: Proportion of rabbits (15 out of 18) showing potentiation50 to 100%: Increase in synaptic response strength after LTP induction200 to 300%: Increase in population spike amplitude1 to 2%: Proportion of total brain protein made up by CaMKII20 milliseconds: Critical timing window for spike timing dependent plasticity1981: Year Morris invented the water maze2014: Year Nabavi et al. demonstrated bidirectional memory control with optogenetics50 years: Anniversary celebrated at the 2023 Royal Society conferenceMemorable Quotes"I stumbled on the phenomenon of long-lasting potentiation quite by accident." (Terje Lomo, on his 1966 observation)"Well in that case you must come to Oslo and see what Terje Lomo has found." (Per Andersen, to Tim Bliss in 1968)"For the first ten years, our paper attracted very little attention." (Tim Bliss, on the initial reception of their 1973 paper)"The NMDA receptor channel has the properties you would want for a Hebbian synapse." (Graham Collingridge)"CaMKII acts as a molecular memory device that can be switched into an active state by a transient calcium signal and then maintain that state long after the signal has ended." (John Lisman, 1994)"A striking parallel between the behavioral and the synaptic effects of AP5." (Richard Morris, 1986)"We c...