introduction to neurobiology of the cns: focus on retina€¦ · 1 september 12, 2018 introduction...
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September 12, 2018
Introduction to neurobiology of the CNS: focus on retina
The retina is part ofthe CNS
Calloway et al., 2009)
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Retinal circuits: neurons and synapses
Sherry, 2002
Rods and Cones
Bipolar cellsHorizontal cells(Mueller Glia)Amacrine cells
Retinal ganglioncells
1. Dendrites
2. Cell body -Soma
3. Axon hillock Axon initial segment
4. Synaptic terminal
Dendrites of post-synaptic cell
Neuron
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Single cell recordingRemote referenceelectrode, outside ofthe cell
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Membrane potentials
• Resting potential (example: -70 mV)
• Hyperpolarize (more negative than resting potential, e.g. -90 mV)
• Depolarize (less negative than resting, e.g -40 mV) – may lead to action potentials.
• Repolarize – return to resting potential
Spiking activity
Depolarization: Greater than resting potential
More neg. than resting potential
Return toresting potential
Membrane potentials
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Integral transmembrane proteins form channels for substances to cross the membrane
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Extracellular & intracellular fluid have different composition of ions (different concentrations)
Resting Ca2+ concentration in the cytoplasm is 10-100 nM
10-7
A cell
Transport across the cell membrane Mechanisms to create and use ion gradients forelectrical signaling
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Membrane permeability – diffusion through the membrane itself is very selective
Non-ion channels
Aquaporins – H2O
Aquaglyceroporinsgasesglycerolsmall uncharged
polar molecules
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AquaporinsWater channels
202003 Nobel Prize in Chemistry
Peter Agre & Roderick MacKinnon
tetramer
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Diffusion, channels and pumps
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Membrane permeability: simple diffusion, channels, carriers, pumps
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Primary active transport: Na+ – K+ ATPase pump uses energy to pump ions against the concentration gradients for the two cations. For every cycle of the pump, 3 Na+ ions leave the cell and 2 K+ ions enter the cell
Secondary active transport uses the gradient created by the pump:co-transport (symport) in this example
OutsideInside
or Glucose
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Active transport: primary and secondary contributes to movement of ions and sugar and amino acids into and out of cells
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Ion concentrations and equilibrium potentials
Berne & Levy
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The Nernst Equation
For calculating equilibrium potentials
Eion (mV)= - 61(mV) x log ( [ion conc]in/[ion conc]out)
-61 = RT/F
The Nernst Equation
Electrochemical equilibriumfor an ion
Eion (mV)= - 61(mV) x log ( [ion conc]in/[ion conc]out)
potassium (K+): -61 X log (150 mM/5 mM) = -91 mVsodium (Na+): -61 X log (14.5 mM/145 mM) = +61 mVchloride (Cl-): -61 X log (115 mM/3.6 mM) = -90 mV
(for neg ion, Cl-) ( [ion conc]in/[ion conc]out
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What is conductance, “g” ?conductance “g” is the inverse of
resistance (R)(g=1/R)
If membrane ion channels are open, resistance (R) is low, and conductance (g) is high
Ohm’s Law E=I*RE = voltageI = currentR = resistance
R= 1/g Resistance (R) = 1/conductance (g)
E=I*1/g; I=E*g
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The chord equation for membrane potential
g
+gNa+ X ENa+
g
The membrane potential will depend on the relative conductances for the major ions and the equilibrium potential for those ions.
gK+ X EK+
Em =
Membrane potentials
• Resting potential (example: -70 mV)
• Hyperpolarize (more negative than resting potential, e.g. -90 mV)
• Depolarize (less negative than resting, e.g -40 mV) – may lead to action potentials.
• Repolarize – return to resting potential
Spiking activity
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Graded (local) potentials and action potentials
Graded potentials are generated via ligand gated channels, They are small and can be hyperpolarizing or depolarizing and they scale in amplitude with the strength of the input.
Action potentials are “all or none” events, that have a threshold, and rely on the presence of voltage-gated channels
Types of channels in membranes Ligand or receptor-activated
Voltage-activated
Stretch-activated
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• Neurons sum and integrate information from their inputs and pass information to the next cell.
• Action potentials (brief impulses) are necessary for signals to travel long distances (e.g. retina to LGN).
• Information is coded in local potentials when axons are short, such as for all cells within the retina except for retinal ganglion cells whose axons form the opticnerve
Impulses and circuits (Hubel no longer on the internet)
Action potential: dominant features
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Local potential and action potential
Linear summation vs threshold
Types of channels in membranes Ligand or receptor-activated
Voltage-activated
Stretch-activated
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Action potential: Tetrodotoxin (TTX) blockade of NaVs
There is no inward sodium (Na+) current
KugelfischPuffer fish
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Action Potential - initiated by depolarization: Conductance (g) changes in voltage-gated channels
Propagation of action potentials
Hubel off line book
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Retina: cells and layersLocal potentials in INL
Action potentials in GCL
Myelin sheath
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II. Synapses for neural signal transmission from cell to cell
Electrical – gap junctions
Chemical – classical pre and postsynaptic membrane- vesicular release
Junctionsbetween cells
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Gap Junctions
Copyright ©2009 The American Physiological Society
Abd-El-Barr, M. M. et al. J Neurophysiol 102: 1945-1955 2009;doi:10.1152/jn.00142.2009
Schematic diagram of 6 rod and cone synaptic pathways(note the gap junctions (ww)
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Chemical Synapse - axodendritic
Chemical Synapse -axodendritic
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Exocytosis - vesicular release and the importance of calcium
Sudhoff – In Ganong Review of Medical Physiology
Receptors
G-protein-mediated signal transduction pathways
Second messengers
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Ionotropic and metabotropic receptors
Ionotropic & metabotropic glutamate receptors
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Synaptic transmission – glutamate is the major neurotransmitter in CNS and retina
Glutamate
Ionotropic(GluR)KainateAmpaNMDA
MetabotropicmGluR
Ionotropic and metabotropic glutamate receptors
Ionotropic Metabotropic
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Retinal glutamate receptor types
Neurotransmitters
m: metabotropic i: ionotropic
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Heterotrimeric G-proteins
Examples of G-protein–coupled receptors and common effectors
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Signal transduction cascades:at each stage, amplification may occur
Gs and Gi: stimulation or inhibition of AC, and formation of cAMP
Beta receptorsEpinephrineNorepinephrine
Dopamine receptors(D1, D3)
Alpha-2Norepi
Dopamine r (D2,D4)
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Phototransduction – a well studied G-protein cascade
Rhodopsin2 adrenergic receptor
Rhodopsin is a G proteincoupled receptor (GPCR)
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Biochemical steps in the phototransductioncascade
Current flow around photoreceptors
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Resources;
Human physiology texts books.
Example:
Physiology 6th edition Chapter 1
Costanzo (In the Health Sciences library, and in the Clinicalkey Database at the TMC library)