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Nervcellsfysiologi HT25.pdf
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Nervcellsfysiologi Textbooks: Bear kap:2-6 Purves kap:2-8 Block 1 Nervcellsfysiologi Eric Hanse
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Action potentials ”in action” www.sciencemag.org SCIENCE VOL 338 5 OCTOBER 2012 Functional cell assemblies, or engrams The withdrawal reflex
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Excitability – the likelihood of evoking action potentials -90 -70 +60 Membrane potential (mV) 10 ms Threshold 0 Excitation Inhibition
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Synaptic and Intrinsic Excitability Synaptic excitation + Intrinsic Excitation + Intrinsic inhibition Synaptic inhibtion Glutamate synapses GABA synapses Na channels Ca channels Extrasynaptic GluRs K channels Cl channels Extrasyn GABARs
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Modulation and Plasticity of Excitability Pl M d Pl M d Pl M d Pl M d Synap excitat Intrin Excitat Intrins inhibiti Synapt inhibtio Plasticity – based on neuronal activity - aims to create / erase engrams Modulation – based on realease of modulatory neurotransmitters – modulate the accessability of engrams
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Electrophysiology – different levels of reductionism Single protein Single synapse Single cell Cell assemblies Isolated cells Cell cultures Brain slices In vivo Patch-clamp recordings Extracellular recordings Network oscillations Brain organoids Optical recordings Multielectrode array recordings
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Membrane potential Na/K-pump & Transporters Equilibrium potentials Membrane potential Selective permeability Ion channels Concentration gradients
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Pumps, concentration differences and equilibrium potential Nernst equation Ejon = 2.303 (RT/zF) log([jon]u/[jon]i) Ejon = 61.54 log([jon]u/[jon]i) Ion concentrations in human cerebrospinal fluid and serum (in mM)
Cerebrospinal fluid Serum Correlation K+ 2.9 4.2 No Na+ 147 140 Yes Cl- 125 100 No Ca2+ Total 1.2 2.4 Yes Ca2+ Free 1.0 1.2
Mg2+ Total 1.2 0.8 No Mg2+ Free 1.0 0.5
Lyckenvik et al (2025) Brain Commun 24:fcaf201
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Ion channels Gating Selectivity Voltage Ligand Ca2+, cAMP, cGMP Temp Mech H+ “leak” Na K N/K N/K/Ca Ca2+ Cl/HCO3
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Leak channels Trends in Pharmacological Sciences (2008) 29:11 The resting permeability for K+ is much higher than for Na+, but the driving force (at resting membrane potential) is much higher for Na+ than for K+. The resultant currents for K+ and Na+ are therefore equal
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Membrane potential -90 -70 +60 Vm (mV) 10 ms Threshold 0 Excitation Inhibition EK ECl ENa Depol Hyperpol RMP Glu GABA Vm = 61.54 mV log PK [K+]u + PNa[Na+]u PK [K+]i + PNa[Na+]i The Goldman equation Repol
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Action potential – ”all-or-none”
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Propagation of the action potential Myelin Diameter Temperatur
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Extracellular recording of action potentials
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Refractory period following the action potential Absolute refractory period = Voltage-gated Na+-channels are inactivated, making a new action potential impossible. Relative refractory period = Voltage-gated Na+-channels de- inactivates during this period and the membrane potential is hyperpolarized. A stronger than normal depol is required to evoke an action potential.
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Optical recording of the action potential Hochbaum et al (2014) All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins Nature Methods 11: 825-833
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Synaptic excitation and inhibition Synaptic excitation + Synaptic inhibtion AMPAR NMDAR Excitatory synapse ”Modulatory Rec” Inhibitory synapse (GABA) ”Modulatory Rec” GABAAR GABABR
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Glu and GABA synapses Input → Output → Cortical pyramidal cell: ca. 30000 Glutamate synapses (90%) ca. 2000 GABA synapses (10%) Megías, Emri, Freund & Gulyás (2001) Neuroscience 102:527 Kasthuri et al (2015) Saturated reconstruction of a volume of neocortex Cell 162: 648661 1 µm
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Presynaptic release of transmitter vesicle SNARE-mediated exocytosis
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Glutamate uptake in astrocytes
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Synapses are usually small and unreliable, but many (and plastic) 3 quantal parameters determine the signalling strength of a synaptic connection Synaptic strength = n x p x q n = no. of release sites p = release probability The probability that an action potential will cause the release of one vesicle q = quantal size The magnitude of the postsynaptic response to one vesicle 2 ms 10 pA Recording from one synapse 1 µm
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- The AMPA receptor channel: -opened by glutamate -permeates Na+ and K+ -gives rise to a brief (ca. 10 ms) EPSP
- The NMDA receptor channel: -opened by glutamate (and Gly/D-Ser) + depol -permeates Na+, K+ and Ca2+
- gives rise to a brief long-lasting (ca. 100 ms) EPSP -is necessary for the induction of synaptic plasticity; Long- term potentiation (LTP) och long-term depression (LTD).
- Metabotropic glutamate receptors (mGluRs) are G- protein coupled receptors that, for example, can give rise to Ca2+ release from ER and facilitate synaptic plasticity. The Glutamate synapse
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The GABA synapse GABAA Rec GABAB Rec
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The i.c. Cl- concentration determines the response of the GABAA receptor channels
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Intrinsic Excitation + Intrinsic inhibition Intrinsic excitability – all ion channels of the neuron, except the ligand-gated in the synapses From Hille ”Ion channels in excitable membranes” E.c. Calcium
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Families of voltage-gated Na+, Ca2+ and K+ channels Voltage-gated K-channels Neuron, Volume 85, Issue 2, 2015, 238 - 256
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Regulation of action potential frequency – AfterHyperPolarisation (AHP) and gKca2+ Nicoll, RA
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Different firing patterns because of differences in intrinsic excitability
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Modulation and Plasticity of Excitability Pla Modu Pla Modu Pla Modu Pla Modu Synaptic excitation + Intrinsic Excitation + Intrinsic inhibition Synaptic inhibtion
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Neuromodulation Co-transmitters ”Classical” ACh, NA, 5-HT, Histamin, DA Co-transmitters Peptides Orexin, Galanin, Endorphin, CCK, VIP, Oxytocin… Retrograde transmitters endocannabinoids, NO, neurotrophins Hormones Cortisol, Estrogen, Progersteron, Ghrelin, Insulin Vasopressin, AF… Gliotransmitters Glu ATP → Adenosine D-serine, Taurine Lactate Neurotransmitters Glu via mGluRs GABA via GABABRs Cytokines, Chemokines TNFα IL-1β…. Modulate: *Release probability *Intrinsic excitability *Plasticity
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Modulation and Plasticity of Excitability Pla Modu Pla Modu Pla Modu Pla Modu Synaptic excitation + Intrinsic Excitation + Intrinsic inhibition Synaptic inhibtion
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Long-term synaptic plasticity (min – years); LTP and LTD