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• Fleiner, Anne Sjøbakken; Kolnier, Daniel; Hagger-Vaughan, Nicholas James; Ræder, Johan & Storm, Johan Frederik (2025). Effects of ketamine and propofol on muscarinic plateau potentials in rat neocortical pyramidal cells. PLOS ONE. 20(1). doi: 10.1371/journal.pone.0316262. Full text in Research Archive Show summary

  Propofol and ketamine are widely used general anaesthetics, but have different effects on consciousness: propofol gives a deeply unconscious state, with little or no dream reports, whereas vivid dreams are often reported after ketamine anaesthesia. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, while propofol is a γ-aminobutyric-acid (GABAA) receptor positive allosteric modulator, but these mechanisms do not fully explain how these drugs alter consciousness. Most previous in vitro studies of cellular mechanisms of anaesthetics have used brain slices or neurons in a nearly “comatose” state, because no “arousing” neuromodulators were added. Here we tested mechanisms of anaesthetics in rat medial prefrontal cortex (mPFC) slices after bath-applying the cholinergic agonist muscarine to partly mimic an “aroused-like” state, using whole-cell patch-clamp recordings from layer 2/3 pyramidal cells (L2/3PCs). According to leading theories of access consciousness and working memory, L2/3PCs are particularly important for these cognitive functions. We found that muscarine induced long-lasting depolarising plateau potentials (PPs) and spiking following brief depolarising current injections in the L2/3PCs. After 2 hours of pre-incubation with ketamine or propofol, the muscarine-induced PPs were altered in seemingly different ways: 3 μM propofol reduced the PPs and (significantly) spiking, whereas 20 μM ketamine seemed to enhance PPs and spiking (non-significantly). Brief wash-in of these drug concentrations failed to induce such effects, probably due to insufficient equilibration by diffusion in the slices. In contrast, pre-incubation with a high dose (100 μM) of ketamine suppressed the PPs and spiking. We discuss whether the apparently different effects on PPs may possibly be related to contrasting clinical effects: ketamine causing atypical anaesthesia with vivid, “psychedelic” dreaming while propofol causes less dreaming.

• Hagger-Vaughan, Nicholas James; Kolnier, Daniel & Storm, Johan Frederik (2024). Non-apical plateau potentials and persistent firing induced by metabotropic cholinergic modulation in layer 2/3 pyramidal cells in the rat prefrontal cortex. PLOS ONE. 19(12). doi: 10.1371/journal.pone.0314652. Full text in Research Archive Show summary

  Here we describe a type of depolarising plateau potentials (PPs; sustained depolarisations outlasting the stimuli) in layer 2/3 pyramidal cells (L2/3PC) in rat prefrontal cortex (PFC) slices, using whole-cell somatic recordings. To our knowledge, this PP type has not been described before. In particular, unlike previously described plateau potentials that originate in the large apical dendrite of L5 cortical pyramidal neurons, these L2/3PC PPs are generated independently of the apical dendrite. Thus, surprisingly, these PPs persisted when the apical dendrite was cut off (~50 μm from the soma), and were sustained by local calcium application only to the somatic and basal dendritic compartments. The prefrontal L2/3PCs have been postulated to have a key role in consciousness, according to the Global Neuronal Workspace Theory: their long-range cortico-cortical connections provide the architecture required for the “global work-space", “ignition”, amplification, and sustained, reverberant activity, considered essential for conscious access. The PPs in L2/3PCs caused sustained spiking that profoundly altered the input-output relationships of these neurons, resembling the sustained activity suggested to underlie working memory and the mechanism underlying “behavioural time scale synaptic plasticity” in hippocampal pyramidal cells. The non-apical L2/3 PPs depended on metabotropic cholinergic (mAChR) or glutamatergic (mGluR) modulation, which is probably essential also for conscious brain states and experience, in both wakefulness and dreaming. Pharmacological tests indicated that the non-apical L2/3 PPs depend on transient receptor potential (TRP) cation channels, both TRPC4 and TRPC5, and require external calcium (Ca2+) and internal Ca2+ stores, but not voltage-gated Ca2+ channels, unlike Ca2+-dependent PPs in other cortical pyramidal neurons. These L2/3 non-apical plateau potentials may be involved in prefrontal functions, such as access consciousness, working memory, and executive functions such as planning, decision-making, and outcome prediction.

• Hagger-Vaughan, Nicholas & Storm, Johan Frederik (2019). Synergy of Glutamatergic and Cholinergic Modulation Induces Plateau Potentials in Hippocampal OLM Interneurons. Frontiers in Cellular Neuroscience. 13. doi: 10.3389/fncel.2019.00508. Full text in Research Archive Show summary

  Oriens-lacunosum moleculare (OLM) cells are hippocampal inhibitory interneurons that are implicated in the regulation of information flow in the CA1 circuit, inhibiting cortical inputs to distal pyramidal cell dendrites, whilst disinhibiting CA3 inputs to pyramidal cells. OLM cells express metabotropic cholinergic (mAChR) and glutamatergic (mGluR) receptors, so modulation of these cells via these receptors may contribute to switching between functional modes of the hippocampus. Using a transgenic mouse line to identify OLM cells, we found that both mAChR and mGluR activation caused the cells to exhibit long-lasting depolarizing plateau potentials following evoked spike trains. Both mAChR- and mGluR-induced plateau potentials were eliminated by blocking transient receptor potential (TRP) channels, and were dependent on intracellular calcium concentration and calcium entry. Pharmacological tests indicated that Group I mGluRs are responsible for the glutamatergic induction of plateaus. There was also a pronounced synergy between the cholinergic and glutamatergic modulation, plateau potentials being generated by agonists applied together at concentrations too low to elicit any change when applied individually. This synergy could enable OLM cells to function as coincidence detectors of different neuromodulatory systems, leading to their enhanced and prolonged activation and a functional change in information flow within the hippocampus.

• Pietersen, Alexander N.J.; Ward, Peter D.; Hagger-Vaughan, Nicholas; Wiggins, James; Jefferys, John G.R. & Vreugdenhil, Martin (2014). Transition between fast and slow gamma modes in rat hippocampus area CA1 in vitro is modulated by slow CA3 gamma oscillations. Journal of Physiology. ISSN 0022-3751. 592(4), p. 605–620. doi: 10.1113/jphysiol.2013.263889. Full text in Research Archive

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• Hagger-Vaughan, Nicholas; Klaus, Carolin & Storm, Johan Frederik (2017). Dual adrenergic modulation of HCN channels in hippocampal and neocortical pyramidal neurons. Full text in Research Archive
• Hagger-Vaughan, Nicholas & Storm, Johan Frederik (2017). Differential basal properties and metabotropic modulation responses between OLM and Martinotti cells. Full text in Research Archive
• Nilsen, Andre Sevenius; Arena, Alessandro; Juel, Bjørn Erik; Storm, Johan Frederik; Murphy, Ricardo & Hu, Hua [Show all 7 contributors for this article] (2017). Forsknigstorget: Hvordan kan hjernen skape bevissthet. Full text in Research Archive
• Hagger-Vaughan, Nicholas & Storm, Johan Frederik (2016). CA1 OLM cells exhibit plateau potentials in response to metabotropic glutamate receptor activation. Full text in Research Archive

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