Neurophysiology 2

Impulse Conduction

2
Communication along
and between neurons:

Graded potentials
and action potentials.

Synaptic potentials
(graded).
A graded potential becomes smaller as it propagates along
a nerve because some of charges leak out of the neuron.

Neuron

Let’s look at the spread of electrical charges.

Passive spread of voltage along nerve axon
Conduction is electronically due to cable properties.

Resistance along axon

causes decay of signal. ,rl
rm
Length constant:
distance over which a
graded electric potential
shows a 63% drop
in amplitude:

l =  rm/rl 63% drop

rm: resistance across

rl: resistance along
Spreading of graded potentials and
initiation of AP.
If graded potential exceeds threshold for
action potential, than action potential is
initiated.
Important:
The further the graded potential spreads
along axon, the further the location of
initiation of action potential along axon.
What happens if membrane depolarization
is caused by action potential?
Propagation of Action Potentials

AP travels along
axon without
decrement in size.

What is
mechanism?
 Look at Action Potential

Voltage change e +50

during AP (130 mv) is x

about 3X as large as t
needed to exceed r
threshold potential a -40

(40 mV):
This extra
depolarization is
called the
“Safety factor”.
 Look at Action Potential

e +50

• This extra x
t
depolarization in AP
r
causes membrane a -40
ahead of AP also to
depolarize and
produce the next
AP!
Na channel
activated

Na channel
inactivated

AP Propagation Domino Effect

Domino Effect
 How to increase passive spread or
velocity of impulse propagation?
l =  rm/rl 1. Get larger rm
2. Get smaller rl
r l = ri + r o
rm ,rl
ri: internal resistance
ro: external resistance =0
Thus: l =  r /r
m i
Answer:
Increase axonal diameter.
 Giant Axons (large diameter or radius) have high
Conduction Speed!
rm is inversely proportional to lateral surface area:
 diameter =>  side surface area =>  leak
channels => less resistance:  rm

ri is inversely proportional to volume:

diameter =>  volume => less resistance:  ri

Effect of increase axon diameter: l =  rm/ri

 rm => l  =>  conduction speed.

 ri => l  =>  conduction speed.
Giant Axons (large diameter or radius) Have High
Conduction Speed!
l =  rm/ri

 rm => l  =>  conduction speed.

 ri => l  =>  conduction speed.
• Do not cancel each other out:
rm is proportional to axonal radius (r ),
ri is proportional to radius2 (r2 )

• Therefore, net effect of increasing radius

of axon is a larger l and an increased
speed of AP conduction!
 Area: 2πrh
Volume: πr2h

Area: 2πrh

Volume (side): πr2h

Area: 2πrh

Volume: πr2h
 Large Diameter Neurons in
Vertebrates

• Disadvantage of large diameter axons:

– Take up a lot of space which limits number of
neurons that can be packed into nervous
system.

– Have large volumes of cytoplasm, expensive to

produce and maintain.

• Solution: Look at electrical insulation of

axons.
 PNS: Schwann Cells

• Wrapped around plasma membrane: myelin sheath.

• Assist regeneration of PNS axons.
 CNS: Oligodendrocytes

• Most common glial cell type.

• Each cell forms myelin sheath around axons in CNS.
• Analogous to Schwann cells of PNS.
• Form supportive network around CNS neurons.
 How to increase passive spread or
velocity of impulse propagation?
l =  rm/rl 1. Get larger rm
2. Get smaller rl
r l =r i + r o
rm ,rl
ri: internal resistance
ro: external resistance =0
Thus: l =  r /r
m i

B: Insulate axon with

myelin: => larger rm
Propagation of Action Potentials

START Here

Myelin is an electrical insulator,

not allowing ions to move across membrane.

Result: push depolarization further down axon.

 Saltatory Conduction

• At Node, depolarization causes Na+ to enter the axon

through open channels, resulting in an action potential.

The depolarization encounters the next node, next

location for AP.
The apparent leapfrogging of APs from node to node
along the axon is called saltatory conduction.
 Multiple Sclerosis
In demylinating diseases, such as multiple
sclerosis, the loss of myelin in the nervous
system slows down the conduction of APs.
Symptoms: muscle weakness, fatigue, difficulty
with walking and a loss of vision.
 Conduction Speed: Summary
Two ways to increase speed:
1. myelin and
2. increasing the diameter of the axon.
Propagation of Action Potentials

Summary: Propagation of AP depends on:

1. Passive properties of membrane
2. Extra depolarization due to AP.
END
Synapse
Communication along
and between neurons:

Synapse: connection
between two neurons.

Two types:
A. Electrical synapse
B. Chemical synapse
Electrical Synapse
 Electrical Synapse
Electrical junction between 2 neurons allows
current from AP in one cell to spread into other
and depolarize it.

Function: Rapid transmission of signals. Faster

than in chemical synapses!

Used in synchronization of electrical activity in

groups of neurons: e.g. vertebrate heart,
oscillations and brain rhythms.

Note: information transfers in both

directions and no control of information
flow!
Chemical
Synapse

Follow
numbers Synaptic
vesicle

Neurotransmitter Ca2+
Chemical
Synapse
Activation Receptors by Neurotransmitter
- NT molecules bind to membrane receptors.
- Receptors are specific for a given NT.
- Ligand – a molecule that binds to another
molecule.
There are multiple receptor types for a
given NT:
Two Main Categories:
- Ionotropic receptors – associated with
ligand-activated ion channels.
- Metabotropic receptors – associated
with signal proteins and G proteins.
Faster Responses at Ionotropic
Receptors
 Slower Responses at Metabotropic
Receptors: A. Direct G-Protein Coupling
Slow Responses at Metabotropic
Receptors: B. Second Messenger
Coupling
 Chemical
Synapse: fast.

1. NT release close
to receptors.

2. Receptors directly
open ion channels
(ionotropic).

3. Small vesicles

Na+
Chemical
Synapse: slow.

1. NT release distant
from receptors.

2. Receptors indirectly
open ion channels
(metabotropic).

3. Large vesicles

Na+
Vertebrate
Neuromuscular
Junction
Study details

Active zone:
are of NT
release
 Modes of Release and Recycling.
1. Docking
2. Priming
3. Fusion

Start

2
3
Synaptic Vesicle Release consists of three
principal steps:
1. Docking
Docked vesicles close to plasma membrane (within 30 nm).
2. Priming
Primed vesicles can be induced to fuse with plasma
membrane by
1. sustained depolarization,
2. high K+ levels,
3. elevated Ca++ levels.

3. Fusion
Vesicles fuse with plasma membrane to release
transmitter in synaptic cleft.
- “Docked” vesicles
Neurotransmitter Release
rapidly fuse with plasma
membrane.
- Protein-protein
interactions, SNARE
proteins, regulate
‘docking’ and Ca2+-
induced membrane
fusion.

SNAREs
In CNS neurons, vesicles are divided into:
1. Reserve pool (80-95%).

2. Recycling pool (5-20%).

3. Readily-releasable pool, RRP, (0.1-2%).

Mild stimulation (few APs, little Ca entry) triggers

NT release from RRP. A small fraction of
vesicles (recycling pool) replenishes the RRP.
Strong stimulation (many APs) causes reserve
pool to mobilize and be released.
Inactivation of Neurotransmitters

e.g. AChE breaks down

Acetylcholine (ACh)

e.g. Norepinehrine (NE)

 Disorders of Synaptic Transmission
• Synaptic transmission: most vulnerable step in neuronal
signaling: could disrupt normal function.
•Examples:
•Parkinson’s disease, schizophrenia, and depression.
• Caffeine, nicotine, alcohol and some common drugs.
• Myasthenia gravis: autoimmune disease where body
fails to recognize the ACh receptor as part of ‘self’ and
produces molecules to attack its receptors.
Receptor destruction causes:
1. diminished excitatory response to ACh.
2. inability of muscle fibers to contract.
Chemical synapses can release more than one kind
of transmitter (e.g. peptide + small transmitter)

An example:
GABA (amino acid)

Somatostatin (peptide)

GABA + Somatostatin
(growth hormone–inhibiting hormone)
Large synapses can have many Active Zones.
Single
Active zone: place of active
zone
NT release.
Synapses can
expand in size to
send a larger signal
to postsynaptic cell.

Synapses increase in
size by forming more
More
active zones, active
although size of a zones
single active zone
can also change..
Inactivation of Neurotransmitters

e.g. AChE breaks down

Acetylcholine (ACh)

e.g. Norepinehrine (NE)

The Major Known Neurotransmitters

Why both?
 Chemical Synapse
Excitatory: AP continues to travel from pre- to
post-synaptic cell: “switch is on”.
Inhibitory: AP arrives at pre-synaptic ending, but
does not travel on to post-synaptic cell:
“switch is off”
Neurotransmitter interacts with postsynaptic
membrane: 2 major events.
A: Transmitter molecule combines with receptor molecule.

B. Occupied receptor sites cause activation of ion

channels.
See example: synapse in vertebrate motor axons.
Recording of muscle AP and Synaptic Potentials

EPSP: Excitatory Postsynaptic Potential.

EPSP precedes
muscle AP
 Synaptic Currents
Binding of neurotransmitter substance to
receptors on postsynaptic membrane results in
opening of postsynaptic channels.

IMPORTANT: Both Na+ and K+ ions can pass

through open postsynaptic ion channel.

Result: 2 simultaneous synaptic currents.

– Inward synaptic current by Na+
– Outward synaptic current by K+

Question: What happens to postsynaptic

membrane potential when both ions move across
membrane?
ACh synapse

Both Na and K
move across
membrane.
 Synaptic Currents
• If only Na ions can move across membrane,
than membrane potential would move to
the Equilibrium Potential for Na+:
ENa (+50 mV).
• Likewise for K+ ions: EK (-70mV).
• If both Na and K ions move across
postsynaptic membrane in opposite
directions, than a new equilibrium will be
established between ENa and EK :
• The Reversal Potential, Erev
Equilibrium Potentials Hyperpolarization
and Reversal Potentials (Vrev)
in a chemical synapse
with Ach as
neurotransmitter.
Vm = membrane potential

If Erev = Vm: no change (3)

Vm = Erev
If Erev > Vm: Depolarization (4)

If Erev < Vm: Hyperpolarization (2)

Thus: the value of reversal
potential is essential in
distinguishing between an
excitatory synapse and Postsynaptic membrane
an inhibitory synapse. Depolarization
 Thus, what is mechanism for
excitatory and inhibitory
synapses?
• Excitatory synapses have a reversal
potential more positive than threshold:
Results in AP (“switch is on”)

• Inhibitory synapses have a reversal

potential more negative than threshold:
Does not result in AP (“switch is off”).
Excitatory (D) and Inhibitory (H) chemical synapses
on same postsynaptic membrane.

Excitatory

Inhibitory
 Summation of postsynaptic potentials:
a. 2 stimuli: No summation, subthreshold: No AP

b. 2 stimuli close together: Summation over time: AP

Temporal summation

Excitatory Inhibitory Excitatory

 Summation of postsynaptic potentials:
b. 2 stimuli, 2 neurons: Summation over space: AP

c. 2 stimuli, excitatory + inhibitory: Summation of EPSP

and IPSP: No AP
Spatial Summation
Excitatory Inhibitory Excitatory
 Synaptic Integration
Summation
Soma and Axon Hillock
Synaptic inputs dendrites
Passive current
flow

Above threshold?

Yes No

Axon Hillock
Action Potential Passive Current
Decays to zero

Conducts down axon

 Presynaptic inhibition:
Inhibitory synapse on top of a excitatory
synapse. Example: Renshaw cells, controlling
overstimulation of muscle cells.
Renshaw cell
 Strychnine Poisoning
• Renshaw cells in spinal cord normally release an
inhibitory neurotransmitter (glycine) onto
motor neurons preventing excessive muscle
contraction.

• Strychnine binds to and blocks glycine receptors

in the spinal cord.

• Massive contractions of all skeletal muscles are

produced, convulsions.
– when the diaphragm contracts & remains contracted,
breathing can not occur!
– Fatal within 3 hours of exposure. No good treatment.
Electrical and Chemical Synapses
Electrical synapse Chemical synapse
Rare in complex Common in complex
animals animals
Common in simple Rare in simple animals
animals
Fast Slow
Bi-directional Unidirectional
Postsynaptic signal is Postsynaptic signal can
similar to presynaptic be different
Excitatory Excitatory or inhibitory
 SUMMARY
PSPs vs. Action Potentials (APs)

EPSPs/IPSPs Action Potentials

• Ligand-gated • Votage-gated
channels channels
• Decremental • Non-decremental
(graded) (non-graded)
• Fast • Conducted more
slowly than PSPs
Neurotransmitters
Acetylcholine Biogenic Amines

Amino Acids

Small-molecule NTs

Purines
Extracellular!
 Peptide NTs: more than 100 peptides,
usually 3-30 amino acids long.

Example: methionine enkephalin, endogenous opioid peptide,

functions as painkiller.
 Receptor background information.
Theory of Drug Action
Drug, Receptor
NT

Agonist
- Every ‘lock’ has its own ‘key’.

If the ‘key’ is not precise, the

‘lock’ does not open.
Antagonist
The ‘drug’ is the key that has to fit
the target specifically and
productively.
 ACh Receptors: 2 Types
1. Nicotinic receptors Agonists (mimics) and
2. Muscarinic receptors Antagonists (blockers).

Agonists

Antagonists
 ACh Receptors: 2 Types
1. Nicotinic receptors Agonists (mimics) and
2. Muscarinic receptors Antagonists (blockers).
Muscle Nicotinic ACh receptor : Ionotropic Receptor
Binding of 2 ACh molecules opens channel through a
conformational change.
Pore is large, and both Na+
and K+ can pass through.
Reversal potential! ACh Na+

K+
Muscarinic Receptor: G-protein activation
Example: Receptor opens a K+ channel directly when its
bg subunit binds to the channel.
The open K+ channel makes cell less excitable by
hyperpolarizing its membrane.

K+

bg subunit
 Autoreceptors
• NT have postsynaptic effect on connecting
cell, but some also presynaptic on same cell!
•

• These presynaptic receptors are called

Autoreceptors (common in CNS).
• Binds NT: same as postsynaptic receptors,
different receptor subtype.
• Decreases NT release & synthesis.
• Acts as a control, “brake”, on NT release
(negative feedback).
Autoreceptors

Where:
Presynaptic.
Somatodendritic.
Terminal.
Effect:
Modulating:
1. Release.
2. Synthesis.
 GABAA Receptor
Highly regulated.
(Ionotropic).
Major Inhibitory NT
- Binds many substances,
including tranquillizers.

Valium, a benzodiazepine,
acts as an agonist:
increasing inhibition.

Cl-
Allosteric Modulation!
Drugs by themselves do not
open channel, but change Function: IPSP
the effect of GABA when both
are present.
Gases: Novel Neurotransmitters.
NOT Packaged in Vesicles!!
But released by presynaptic terminals!

• Nitric oxide (NO)

– A short-lived toxic gas; diffuses through post-
synaptic membrane to bind with intracellular
receptor (guanylyl cyclase), producing cGMP.
– Involved in vasodilation, learning, memory.
– Some types of male impotence can be treated by
stimulating NO release (Viagra).

• Carbon monoxide (CO) is a main regulator of

cGMP in the brain.
 SUMMARY
• Synthesis depends on type of enzymes in
neuron.
– Can be amino acids, made from amino acids or their
derivatives, or peptides.
• Action potential triggers release: exocytosis.
• Bind to receptors (metabotropic or ionotropic) to
induce changes.
• Reuptaken or broken down or diffusion to stop.

• Note: some neurotransmitters are also released

in other parts of the body and not just by
neurons (5-HT, Epinephrine, NO)
END