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Neuroscience with Pharmacology 2Functions and Mechanisms of Nerve Conduction
“Cogito, ergo sum” “I am a machine!”
The monosynaptic stretch reflex
Initiation Conduction Transmission End effect
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1. Types of neurones and glial cells; “dynamic polarisation” of neurones; slow conduction by axonal transport
2. Extracellular recording, fast conduction by action potentials, conduction velocity and function in myelinated and unmyelinated axons; refractory period.
3. Ionic mechanisms and pharmacology of action potentials and ion channels
1. Types of neurones and glial cells; “dynamic polarisation” of neurones; slow conduction by axonal transport
2. Extracellular recording, fast conduction by action potentials, conduction velocity and function in myelinated and unmyelinated axons; refractory period.
3. Ionic mechanisms and pharmacology of action potentials and ion channels
The nervous system is composed of neurones, gliaand blood vessels
Cerebral Cortex CorticalPyramidal cell
CerebellarPurkinje cell
Neurones are diverse in form and function.
DRG : sensoryneurone
Cerebellum:Purkinje neurone
Spinal Cord:motor neurone
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Neurones also differ in the neurotransmitter molecules they secrete
glutamate
AcetylcholineGABA
glycine
astrocyte
oligodendrocyte (CNS) or Schwann cell (PNS)
Astrocytes, oligodendrocytes and Schwann cells are importanttypes of neuroglia
Importance of the Axon
SOMA AXON SYNAPSE
COMPARTMENTAL MODEL OF THE NEURON
Dendrites
Information
(“dynamic polarization” - S. Ramon y Cajal)
Motor neurones are among the largest cells in the body, withaxons that extend many times the diameter of their somas
12,600 km
384,000 km
3,475 km
Pacificisland(5km)
0.5km
RobertHartley/Adrianna Teriakidis
The (mouse) motor neurone in perspective
500 µm
50µm
27,412 µm3
Vr=1
5,88
2 µ
m3
Vr=30
2,377 µm3
Vr=4
100µm
3 cm
30µm
4DL muscle
Proteins of the axonal cytoskeleton
20 nm10 nm 5 nm
Microtubule Neurofilament Microfilament
ActinTubulin
Axonal Transport
Nucleus
Rough ER
Golgiapparatus
Synapticvesicles
Organelles
2
Active peptidePrecursorpeptide
13 4
Axonal transport of organelles and trophic factors
Kieran et al. J. Cell Biol. 2008:169:561-567© 2008 Kieran et.al.
time
distance
“Slow” axonal transport :1-8 mm/day~ 0.2 mm/hr~ 0.05 µm/sec
Molecular signals, structural proteins and organelles are transported along the axonal cytoskeleton
Orthograde (kinesin motors)
Retrograde (dynein motors)
“Fast” axonal transport :100-400 mm/day~ 5-20 mm/hr~ 1-5 µm/sec
1. Types of neurones and glial cells; “dynamic polarisation” of neurones; slow conduction by axonal transport
2. Extracellular recording, fast conduction by action potentials, conduction velocity and function in myelinated and unmyelinated axons
3. Ionic mechanisms and pharmacology of action potentials and ion channels
1. Types of neurones and glial cells; “dynamic polarisation” of neurones; slow conduction by axonal transport
2. Extracellular recording, fast conduction by action potentials, conduction velocity and function in myelinated and unmyelinated axons; refractory period.
3. Ionic mechanisms and pharmacology of action potentials and ion channels
ca 1800: Galvani and Volta demonstrate the electrical excitability of nerve
ca. 1815
Stimulatingelectrodes
Recordingelectrodes
Clinical Electromyography
Increasing stimulus intensity“recruits” (activates) more axons
Extracellular recording reveals multiple “fibre groups”
S
ms
mV
Erlanger & Gasser (1930)
First recordings of “compound” action potentials in bullfrog sciatic nerves
Fibre Groups A,B,C
Aα
Bβ
Cγ D
δ
Increasing stimulus intensityactivates axons of different types(“modalities”)
Cross sections of nerves show myelinated andunmyelinated axons of wide-ranging diameter
50µm
The myelin sheath
2 µm
Cross sections of nerves show myelinated andunmyelinated axons of wide-ranging diameter
Cross-section of HumanPeripheral Nerve
Aα
Aδ
Myelinated Nerve FibreDiameter Spectrum
Development of the myelin sheath
Myelin sheath and node of Ranvier
Node ofRanvier
Myelinsheath
K / Na / Caspr
Copyright © motifolio.com
Saltatory conduction
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Myelinsheath
Node ofRanvier
Axon
7111143
t=0
Unmyelinated Myelinated
<0.5 m/second 2-100 m/second
Conduction velocity =
Distance (m)Latency(s)
Myelination optimises nerve conduction
The “g-ratio” is roughly constant (0.6) inmyelinated axons
Refractory period
No action potential can occur during the absoluterefractory period. A stronger stimulus is requiredduring the relative refractory period
1. Types of neurones and glial cells; “dynamic polarisation” of neurones; slow conduction by axonal transport
2. Extracellular recording, fast conduction by action potentials, conduction velocity and function in myelinated and unmyelinated axons
3. Ionic mechanisms and pharmacology of action potentials and ion channels
1. Types of neurones and glial cells; “dynamic polarisation” of neurones; slow conduction by axonal transport
2. Extracellular recording, fast conduction by action potentials, conduction velocity and function in myelinated and unmyelinated axons; refractory period.
3. Ionic mechanisms and pharmacology of action potentials and ion channels
Initial Segment
http://tainano.com/chin/Molecular%20Biology%20Glossary.htm
The action potential propagates as a wave of depolarisation,due to switching from closed,open and inactivated states involtage-gated ion channels.
The action potential recorded intracellularly (squid giant axon)
Resting potential
Threshold
Upstroke: DepolarisationOvershoot
Downstroke: Repolarisation
Afterhyperpolarisation
Refractory Period
Stimulus artefact
Em=RT
F.Ln
(Pk.[K
+
]o+ P
Na.[Na
+
]o+ P
Cl.[Cl
!
]i)
(Pk.[K +]
i+ P
Na.[Na+]
i+ P
Cl.[Cl !]
o)
Na+
K+
Inside Outside
Cl-
Goldman- Hodgkin-Katz(GHK;or “Goldman”) Equation
Membrane potential is determined by selective permeability and ion gradients
1950-55: The “sodium hypothesis”
1. Low sodium reduces AP
[Na+]o
2. “Voltage-clamp” analysis reveals transient inward currentscarried by sodium ions and delayed outward currents carriedby potassium ions when membranes are depolarised.
Alan Hodgkin
AndrewHuxley
BernardKatz
Erwin Neher Bert Sakmann
1976: Neher & Sakmann make the first recordings from single ion channels
T=0 ms; Rest
Na+
- -- -
m
h
K+
n
- -- -
T=1 ms; Activation
Na+
+ ++ +
K+
T=2 ms; Inactivation/Rectification
Na+
- -+ +
K+
-- -
- -- -
T=4 ms; Absolute Refractory Period
Na+
K+
-- -
- -- -
T=5-10 ms; Relative Refractory Period
Na+
K+
-- -
T=20 ms; Recharged = Rest
Na+
- -- -
K+
Voltage-sensitive ionic currents are blocked by specific drugs
Channel Antagonist/blocker
Na+ currents tetrodotoxin (TTX)lignocaineµ-conotoxin
K+ currents tetraethylammonium (TEA)4-aminopyridine (4-AP)Cs+
Ca2+ currents Cd2+, Co 2+ , Mg2+
L-type dihydropyridines (DHP) N-type ω-conotoxin P-type ω-agatoxin
1. There are several types of neurones and glial cells. Neurones show“dynamic polarisation”. The function of axons is to carry information: fromthe soma-dendritic compartment to the axon terminals; and from axonterminals to cell bodies.Axonal transport along cytoskeletal proteins carries orthograde andretrograde signals, molecules and organelles slowly, at velocities of~ 0.05 µm/sec (slow axonal transport) to ~ 5 µm/sec (fast axonaltransport).
2. Extracellular recording and microscopy show that action potentialconduction in axons is determined by their diameter and myelination(oligodendrocytes in the CNS, Schwann cells in the PNS).Axon membranes conduct action potentials rapidly, at ~0.5-100 m/sec.
3. Ion channel properties explain AP shape, threshold, all-or-nothingresponse and refractory period.Voltage-clamp analysis and pharmacology show that ion channels in axonmembranes have specificity (Na, K, Ca) and voltage- and time-dependentpermeability.
Summary