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Lecture 3

Lecture 3 Notes.docx

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Rutsuko Ito

Lecture 3 Notes Synaptic integration and neuromodulation Principles of synaptic integration Principles of synaptic integration: Majority of central neurons receive input from 100s of neurons (excitatory and inhibitory). AP firing depends on whether the membrane potential at the spike trigger zone is above or below threshold. Thus, AP in central neuron is triggered only after the integration of 1000s of EPSPs and IPSPs generated at different parts of the complex dendritic tree, which travel down to the axon hillock. Synaptic integration: Usually presented as a relatively simple algebraic process whereby EPSPs and IPSPs add up to determine the membrane potential at the spike initiation zone. Dendrites are considered conduits delivering synaptic potentials to the site of integration (traditional view) Temporal summation: If a synaptic input occurs before a previous potential has decayed, the two will summate (add up). In this way, high frequency excitatory inputs can produce large summating EPSPs Spatial summation: If two synapses are located close together, simultaneous inputs will summate. Conversely, if they are distant from each other, the potentials may decay before they meet. So spatial summation cannot occur. Amount of excitation / inhibition contributing to generation of AP depends on a number of variables: 1) Where a synaptic input is located relative to the spike initiation zone, which in turn depends on the branching architecture of the dendritic tree (how far away). 2) Where a synaptic input is located relative to active dendritic conductances. 3) The backpropagation of action potential. 4) Where the synaptic input is located relative to other EPSP / IPSPs (synaptic placement). 5) The frequency of the synaptic input. 6) The initial size of the EPSP / IPSP. The passive decay of EPSPs over distance determines the magnitude at the spike trigger zone The passive decay of EPSPs over distance determines the magnitude at the spike trigger zone: EPSPs and IPSPs decay with distance from their point of origin at synapses. PSPs arising from distal synapses may decay more and so contribute less depolarization or hyperpolarisation at the spike initiation zone. Dendritic cable theory: Dendrites can be likened to spatially extended, branched electrical cables that are subject to the laws of cable theory. If the propagation of PSPs is to rely solely on the passive electrical properties of dendrites (as a passive cable), then we are likely to see a decay of the PSP along the dendrite. Rate of PSP decay relies on a number of factors: 1) Length constant (electronic length). 2) Time constant. 3) Dendritic morphology. Length constant: The length of the membrane over which a synaptic potential decays to 36% of the initial value. Long length constants facilitate spatial summation because EPSPs decay less over distance. The length constant itself depends on the ratio of the membrane resistance (Rm) to the resistance of the intracellular space (Ri - internal axial resistance. The axial resistance (Ri) is determined by the specific resistance of the cytoplasm and the diameter of the central core (Ri is high when the dendrite is thin). Membrane resistance (Rm) describes how leaky the membrane is (the membrane becomes leakier as more channels open, thus Rm decreases). Therefore, a long length constant is achieved when Rm is high and Ri is low. Time constant: Describes how fast PSPs change or decay in time. If an EPSP decays slowly, there is greater temporal window for summation with the next EPSP. The time constant depends on Rm and Cm (membrane capacitance). Cm is usually of a fixed value (thickness of membrane) so the time constant is more likely to fluctuate in accordance with Rm. The greater the time constant; 1) The longer it will take to reach maximal voltage change, 2) The slower the decay of the voltage. Membrane capacitance: The lipid bilayer in a cell's membrane acts as a capacitor which stores electrical charges that are equal and opposite on either side of the membrane. Its value depends on the thickness of the membrane (the closer together the charged plates, the higher the capacitance). Dendritic morphology: 1) If an EPSP spreads from a synapse toward a closed end or a branch that is much finer than that to which the synapse contacts (tapering), their decay is less than predicted (i.e. decay is slower as it travels towards a tapered point). 2) If the EPSP spreads towards an expansion, the spatial decay is more extreme. Implications of dendritic morphology on EPSP decay: Spatial decay is direction dependent or asymmetric. An EPSP will decay more over the same distance as it spreads toward the cell body from a dendrite (expansion) than as it spreads towards the tip of a branch (tapering). Scaling mechanism of dendrites: Compensates for the disadvantage of being located further away from soma (cell body). At more distal sites, the PSP response to synaptic input has a higher amplitude than the PSP response to synaptic input at more proximal sites to the cell body. Magee and Cook / Dendritic democracy: Found that the further away the synaptic location was from the soma, the bigger the size of the EPSP. Dendritic democracy reflects the idea that the 'vote' of the distal synapse in deciding the outcome of an axonal output counts as much as a proximal synapse. What mechanisms may underlie the amplitude normalization? What mechanisms may underlie the amplitude normalization?: 1) Based on morphological feature of distal dendrites (tapering) vs proximal dendrites (more expansive). Larger Ri (internal resistance) and lower local Cm (surface area) act together to increase amplitude of local voltage response. V=IR. 2) Distal synapses have increased density of post-synaptic receptors (particularly AMPA receptors). Magee and Cook / Dendritic democracy?: Compared real dendritic EPSPs to simulated dendritic EPSPs based purely on dendritic morphology. 1) In layer 5 neocortical pyramidal neurons, the somatic impact of dendritic EPSPs is constrained and there is absence of dendritic democracy. Probability of AP generation determined by proximal / basal dendritic tree. 2) In CA1 hippocampal pyramidal neurons, clear attenuation (reducing) of amplitude with increasing distance with site-independence of somatic EPSP. Suggesting dendritic democracy (equality of dendritic EPSP impact on AP output). Conclusion?: Dendritic morphological properties alone are not sufficient to account for the scaling mechanism. Pettit and Augustine / Post-synaptic density: Examining whole cell patch clamp recordings with use of photolabile 'caged' glutamate release at different distances from cell body. Observed increased AMPAR mediated current density at the furthest sites away from the cell body in the apical dendrites. Active conductances in dendrites can amplify EPSPs Active conductances in dendrites can amplify EPSPs: Dendrites are not purely passive cables. They possess voltage sensitive conductances that can generate spikes (mediated by voltage gated Na+ and Ca2+ channels). Dendritic excitability: Depends on the distribution of voltage gated ion channels (Na+, Ca2+) along the dendrites in addition to dendritic morphology (tapering vs expansion). Distribution of Na+ and Ca2+ channels: In hippocampal pyramidal neurons, Na+ channels are located more proximally (basal sites). Ca2+ channels are more distal (apical sites). Purkinje cells in the cerebellum do not express a large number of voltage gated Na+ channels in dendrites. Consequence of active dendritic conductance: EPSP summation can take place non-linearly. Supralinear summation: Generation of a combined EPSP that is larger than the algebraic sum of two EPSPs generated from two different synaptic inputs. Can occur as a result of recruiting Na+ and Ca2+ conductances. Nettleton and Spain / Spatial supralinear summation: Demonstrated summation of an EPSP from proximal dendritic site and an EPSP from a distal dendritic site (different l
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