Physiology of Excitable Cells - Synaptic Integration

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Purpose of chemical synapses
inormation transfer between cells, amplification of signals, integration of multiple inputs, plasticity - learning and memory
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Neuronal function
can generate intrinsic activity, recieve inputs from other neurons via synapses, integrate recieved synaptic inputs, encode patterns of activity for output, distribute outputs to other neurons via synapses
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Monosynaptic reflexes
involve only one central synapse in spinal cord grey matter between afferent and efferent neurons - consists of only two neurons one sensory and one motor neuron
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Polysynaptic reflexes
one or more interneurons connect sensory and motor signals. Important to ensure 2 muscles arent active at the same time - inhibit opposing muscle
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EPSP
transmitter opens ion channels permeable to Na+ or Ca2+, as theres a higher conc outside cell Na+/Ca2+ enter cell by electrochemical gradient - membrane potential becomes less negative - excitatory postsynaptic potential
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IPSP
transmitter opens ion channels permeable for K+. as there is a higher conc of K+ inside the cell K+ efflux - membrane potential becomes more negative - inhibitory postsynaptic potential
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IPSP 2
transmitter opens ion channels permeable to Cl-, the concentration of Cl- is higher outside the cell so Cl- enters the cell making membrane potential more negative - inhibitory post synaptic potential
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Ionic basis of EPSPs and IPSPs
EPSP - due to cation influx - depolarisation, IPSP - due to anion influx or cation efflux - hyperpolarisation
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3 important ligand gated ion channel families in neurons
Cys-loop receptors - nicotinic Ach, glycine, GABA, Ionotropic glutamate receptors - NMDA, AMPA, P2X receptors
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Cys loop receptor superfamily
includes E -nAch, I - GABAa + Glycine, 4 transmembrane subunits - 5 subunits form pore allowing ions to cross. Pore formed by M2 segments. E - -ve charged aa residues at surface attracting +ve charged. I - +ve charged aa residues -selectivity for -ve
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conversion of + selective receptors to - selective receptors
Glycine receptor - conversion at point 1, deletion at position 2, conversion position 13 - mutated glycine receptors - cation selective
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conversion of - selective receptors to - selective receptors
nAch receptor - conversion position 1, conversion position 13, insertion position 2 - mutated Ach receptor is anion selective
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EPSP vs AP
EPSPs caused by Na+ influx (ligand gated), APs caused by Na+ influx (voltage gated). EPSPs smaller than APs - lower number of synaptic ligand gated channels and differences in biophysical properties of channels
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Ligand gated vs Voltage gated ion channels
ligand gated not solely permeable to Na+, also Ca2+ and K+ when open influx of Na+ but also outflow of K+. voltage gated - highly selective only let Na+ through. Consequence for ion selectivity -resting potential for voltage- close to Equipote of Na+
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Why is synaptic integration important?
neurons recieve and provide multiple synaptic inputs to the same and/or different neurons - synaptic integration enables info processing in CNS and integration of these inputs determines nervous system function
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Parameters effecting synaptic integration
Neuronal morphology and synapse distribution (distance and position), Synaptic properties (multiple inputs required to depolarise and trigger AP), Membrane properties (length constant affects spatial, time constant affects temporal)
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Spatial Integration
integration of postsynaptic potentials that occur in different locations but at the same time - combined effect - spatial summation
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Temporal integration
integration of post synaptic potentials that occur in the same place but at different times - temporal summation
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Where does spatial integration matter?
one neuron - many contact sites (pre synaptic AP activates multiple synaptic contact sites simultaneously), many neurons - simultaneous activity ( acitivity in 1+ neuron coincides - multiple synaptic contact sites activated simulataneously)
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Purkinje cells
important - integrating neurons in cerebellum, Parallel fibre input: single contact - small synaptic current and potential, Climbing fibre input: many contacts - large synaptic current and potential
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Why length constant affects spatial synaptic integration
amplitude of potential change reduces with distance from synapse, decline in synaptic amplitude with distance determined by length constant. Vm = Vepspmax x e-(x/length constant)
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Temporal integration and time constant
Short PSP - no temporal summation, Long PSP - temporal summation. Decay of PSPs - T - to decay from peak to 37%, mainly dependent on membrane properties - Vm = Vepspmax x e(-t/T)
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Time constant
T = Rm x Cm greater Rm synaptic current doesnt leak as rapidly, greater Cm - more charge - PSP lasts longer
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Temporal integrator
long time constant, majority of EPSPs contribute to activation of action potentials - precise timing of APs only weakly linked to input pattern - less important
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Coincidence detector
short time constant - only few EPSPs contribute directly to activation of APs - timing of APs closely linked to coincident synaptic inputs
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Integration of EPSPs and IPSPs
1. excitatory and inhibitory synapses on different dendrites at same distance from soma = linear summation of currents - combined effect positive depolarisation + negative hyperpolarisation
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2. Inhibitory synapse between Excitatory synapse and soma on same dendrite - summation effects no longer linear. Two effects, either current flow that counteracts current flow E, opening ion channels lowering Rm changing length constant -> NON linear
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Uncoupling of dendrites by inhibitory synapses
2 excitatory and 1 inhibitory synapse. inputs on seperate dendrites integrated by soma, inhibitory synapse can block propagation - function uncoupling of dendrites - prevents integration of synaptic inputs recieved by seperate dendrites
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Silent postysynaptic inhibiton
neurotransmitter binds to receptor, opening of post synaptic ion channels, change in Rm but no current flow and no change in membrane potential
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Inhibitory shunt
lower Rm when both synapses are active - change in memnbrane potential is smaller - reduces excitatory potential by division rather than linear subtraction
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Studying integration
Using photo release of 'caged' glutamate to stimulate effect of glutamate release at individual synapses. The overall effect of synaptic inputs strongly dependent on order/precise timing of synaptic inputs
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Synaptic facilitation
form of short term plasticity that enhances synaptic transmission. It occurs when 2nd AP produces larger EPSP than 1st AP
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Synaptic depression
When 2nd AP produces smaller EPSP. Attributed to the depletion of readily releasable vesicles
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Paired-pulse facilitation - presynaptic model
1st AP:Ca2+ influx, release of transmitter from some vesicles, priming of other vesicles. After 1st AP:1st AP caused increase in number of primed vesicles. 2nd AP: Ca2+ influx - more transmitter release
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Synaptotagmin 7
Synaptotagmins are calcium sensors important for synnaptic vesicle release, Jackman - evidence that synaptotagmin 7 plays essential role in synaptic facilitation but not important for basic synaptic vesicle release.
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Spike Broadening
If neuron active repeatedly - fatigues and they get slower and broader, longer for cell to repolarise - Ca2+ gated voltage channels open longer. Repetitive firing can lead to spike broadening - more transmitter release + increased synaptic response
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Paired-pulse depression - presynaptic model
some synapses- repeating firing of presynaptic leads to progressively weaker postsynaptic. 1st AP:Ca2+ influx, release of docked vesicles, After - 1st AP caused depletion of docked vesicles. 2nd AP: Ca2+ influx - few docked vesicles ready for release
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Postsynaptic modulation
modulatory input alters sensitivity of postsynaptic membrane to presynaptic transmitter release
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Presynaptic modulation
modulatory input alters presynaptic transmitter release 2 examples: presynaptic inhibition and presynaptic facilitation
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probability
Synapses with low release probability more likely to show synaptic facilitation and synapses with high release probability more likely to show synaptic depression
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Example - altering number of postsynaptic receptors
GABAa receptors assembled in endoplasmic reticulum and packaged into vesicles in Golgi apparatus. Insulin promotes insertion of GABAa receptors in postsynaptic - increase. BNDF promotes removal of GABAa receptors -decrease in postsynaptic- small resp
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Presynaptic inhibition
presynaptic mechanism of heterosynaptic modulation. Reduced presynaptic Ca2+ influx - reduced transmitter release - reduced receptor activation
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Heterosynaptic facilitation
presynaptic mechanism for synapse strengthening. Works by: 5-HT activates metabotropic 5-HT receptor - activates AC - increase cAMP-activates PKA-phosphorylates K+channel-reduction K+-broadening of AP-more Ca2+ influx-more transmitter release
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Mechanisms of synaptic modulation
PRESYNAPTIC: altered vesicle entry, altered Ca2+ entry, altered vesicle recycling. POSTSYNAPTIC: altered receptor function, altered receptor number
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Long term synaptic plasticity
long term potentiation first discovered in hippocampus, hippocampus important for learning. patient HM
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Forms of long term synaptic plasticity
long term potentiation - peristent strengthening of synapses. Long term depression - reduction in the efficacy of neuronal synapses
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Card 2

Front

can generate intrinsic activity, recieve inputs from other neurons via synapses, integrate recieved synaptic inputs, encode patterns of activity for output, distribute outputs to other neurons via synapses

Back

Neuronal function

Card 3

Front

involve only one central synapse in spinal cord grey matter between afferent and efferent neurons - consists of only two neurons one sensory and one motor neuron

Back

Preview of the back of card 3

Card 4

Front

one or more interneurons connect sensory and motor signals. Important to ensure 2 muscles arent active at the same time - inhibit opposing muscle

Back

Preview of the back of card 4

Card 5

Front

transmitter opens ion channels permeable to Na+ or Ca2+, as theres a higher conc outside cell Na+/Ca2+ enter cell by electrochemical gradient - membrane potential becomes less negative - excitatory postsynaptic potential

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