NEUROPHYSIOLOGY

Elmer A. Linao M.D. MBA, FPCP, FPCC, FAsCC

Chair, Department of Physiology
• NEURON
• Learning Objectives:
• • List the 6 tenets of the Neuron Doctrine
• • Describe how the neuron resting membrane
potential is generated
• • Discuss how the a neuron action potential is
generated and propagated
• • Discuss the types, structure of synapses
• • Discuss the major neurotransmitters
• Amount to 100B
• • Terminally differentiated cells derived from
primitive neuroblasts
• General Appearance
• Cell body: maintains the integrity of the
whole neuron

• Processes:
• Dendrites: receive signals
• Axons: transmits signals
• Process of transporting materials
• Cell body to terminal portion

• Types of transport
• Fast transport – uses protein kinesin
• Slow transport
• Fast Retrograde Transport – uses protein dynein
 The Neuron Doctrine
• by Santiago Ramon y Cajal (1887) summarizes neuron
structure and function. 6 tenets:
• 1. Anatomical
• The neuron has a karyon, perikaryon, axon and dendrites
• 2. Functional
• basic unit of the nervous system capable of receiving a
stimulus, generating and transmitting a nerve impulse
• 3. Polarized
• when stimulated under normal conditions it conducts
impulses in one direction, from dendrite to synaptic endings
4. Genetic
• develops from a neuroblast, it contains genetic code
which specifies its structure, metabolism and connections
• 5. Pathologic
• Each neuron reacts to injury as a unit. If severely
injured the whole neuron will die as a unit
6. Regenerative
• although neurons a permanent cells, some may grow
new axons if the axon is severed particularly in the PNS
Basic Schema of the Nervous System:
What is Potential?
• -A field defined in space, from
which many important physical
properties may be derived.
• - Constant Electrical difference.
• Every cell has a voltage (difference in electrical charge)
across its plasma membrane:
 Range is -50 to -90 mV [about -70 mV
(millivolts)] in all species investigated
• the relative vicinity inside of the cell is
negative with respect to the outside.
• All cells of the body need electrical
potential to be able to function.
• Voltmeter- placed with one electrode inside the axon and
the other outside the membrane reads the voltge.
Membrane Potential (Vm) or
Transmembrane potential

- The difference in voltage (or

electrical potential difference)
between the interior and exterior of
a cell (Vinterior − Vexterior)
Why is there a membrane potential in
a cell?

Because of the differential

distribution of positive & negative
charges across a membrane.
Membrane has no potential

Membrane has a potential

What maintains the separation of
charges?
• It is because of the lipid bilayer of the cell membrane
which blocks the diffusion of ions creating an asymmetric
ionic distribution . This separation creates a difference in
potential or voltage across the membrane called
membrane potential.
Diffusion Potential

• - The tendency of the ion to move out of the cell.

• - Because of their chemical concentration, a force
develops that tends to move the ions from a higher
concentration to a lower concentration.
• Why? Because the ion involved want to achieve
equilibrium:
• - K - wants to move down its concentration gradient, so it
diffuses out of the cell into the ECF .
• - Na wants to move down its concentration gradient to
achieve equilibrium so it diffuses from the Outside of the
cell into the ICF.
• - If the diffusion is allowed to continue, EQUILIBRIUM will
be achieved.
Equilibrium or Nernst Potential
• - the diffusion potential of a membrane that exactly
opposes the net diffusion of a particular ion through the
membrane.
• - Force that opposes the movement or diffusion
potential
• - Because of the large potassium concentration
gradient from inside toward outside, there is a strong
tendency for extra numbers of potassium ions to diffuse
outward through the membrane. As they do so, they
carry positive electrical charges to the outside, thus
creating electropositivity outside the membrane and
electronegativity inside because of negative anions that
remain behind and do not diffuse outward with the
potassium.
• Within a millisecond or so, the potential difference
between the inside and outside, called the diffusion
potential, becomes great enough to block further net
potassium diffusion to the exterior, despite the high
potassium ion concentration gradient. In the normal
mammalian nerve fiber, the potential difference required is
about 94 millivolts, with negativity inside the fiber
membrane.
• From the Picture above:
• In K- relative vicinity of the cell, if the charge reaches -
90mV, prevents further efflux of potassium out of the cell.
• In Na- If it reaches -60mV, prevents further influx of
sodium.
• REMEMBER!
• Magnitude of the Nernst potential = ratio of the
concentrations of the ion on either side of the membrane.
• Greater Ratio = Greater Nernst Potential.
• Equilibrium Potential is based on the charge INSIDE the
cell.
Ionic composition of cytoplasm and
extracellular fluid

• Fixed Ions: PROTEINS

• NUCLEIC ACIDS
• There are fixed anions intracellularly that cannot diffuse
due to their size. These fixed anions are negatively
charged.
Nernst Equation
• can be used to calculate the Nernst potential for any
univalent ion at normal body temperature of 98.6°F (37°C)
• Nernst equation is used to get the equilibrium potential
of an individual ion.
Requirements for Nernst Equation:
• - Has to be one species and has to be diffusible
• - Semipermeable membrane
• - Diffusion pressure
• - Electrical pressure
Physiologic Significance of the
Membrane Potential
• No membrane potential, no action potential will be
generated.
• No membrane potential, no returning of ion channels to
inactive states.

The normal generation of action potentials depends on a

normal physiological value of the resting membrane
potential.
The normal generation of action
potentials depends on a normal
physiological value of the resting
membrane potential.
Importantly, the voltage-gated Na+ channels
of neurons, skeletal muscle, and cardiac
muscle cells enter an inactivated, non-
conducting state after opening, and cannot
reenter the open state without first
recovering from inactivation (see figure
above). Recovery from inactivation is a
voltage-dependent process that takes place
at membrane potential values more negative
than the threshold voltage.
Thus, the return of the membrane potential to the resting
value is critical for allowing these channels to continue to
function properly. If due to a pathophysiological condition
(such as elevated extracellular K+ levels), the resting
membrane potential approaches the threshold potential for
neuronal and muscle voltage-gated Na+ channels, the
channels would enter the inactive state, from which they
cannot recover. The consequence of this will be
devastating for the organism in that neurons can no longer
fire and cardiac myocytes can no longer contract to pump
blood through the circulatory system.
Resting membrane Potential (RMP)
• potential difference across the axon plasma membrane of
a neuron not sending signals (not firing).
• At a Resting Potential, a membrane is said to be
polarized.
• The ( + ) outside and ( - ) inside of the the relative vicinity
cells are maintained.
REMEMBER!
• 3 Important Mechanisms by which RMP is generated:
• 1. Transmembrane K+ gradient thru non-gated K+ leak
channel
• 2. Donnan effect
• 3. Na-K ATPase pump
1) Transmembrane K+ gradient thru non-gated K+ leak
channel
Most important and major contributor in resting
membrane potential. WHY:
- K+ channels are continuously open ( doesn’t need
voltage, ligand).
- Selective permeablilty of Cell membrane to
Potassium.
Goldman- Hodgkin- Katz Voltage
Equation
• Use to measure the actual value of RMP
• Utilizes the concentration and permeability of ALL THE
IONS involved.
• More accurate.
2) Donnan effect
• more important in maintaining ion concentration gradient.
• In the presence of a non-diffusible ion, diffusible ions distribute
themselves so that at equilibrium, their overall concentrations are
equal.
• Based on random movement of the molecules that tends to scatter
them evenly within a given volume (Brownian motion)
• Net movement from high to low concentration
• Net movement stops when concentration is equal throughout
(diffusional equilibrium)
• However the presence of non-permeant proteins (negatively
charged) inside the cells will limit diffusion of Cl- down its
concentration gradient (BUT there will STILL be movement of
Cl into the cell but will not reach its diffusional equilibrium)
• This will then cause the vicinity inside the PM to be electrically negative
compared to outside vicinity (because of the Cl- that entered the cell)
• More importantly, the positively charged potassium ions will now tend to
go inside the cell because of the more negatively charged inside vicinity
of the PM
• Similarly, two forces are created – one that is pulling potassium in
(because of the charges: electrical gradient) and one that is pulling it out
(because of the concentration: chemical gradient)
• Eventually, to maintain electrical neutrality on each side, there will
always be a greater [K+] inside and a greater [Cl-] outside
(Asymmetric distribution due to Donnan
Effect)
• Effect: Asymmetric distribution of permeant ions at
equilibrium results to an electrical difference across the
membrane, the magnitude of which can be determined by
Nernst Equation
3) Na-K ATPase pump

• - Contributes only about 20%

• - Epectronic pump
• - Atp hydrolysis
• - 3 Na – pumped out
• - 2 K+ - goes in
• - Maintains the membrane potential.
• - Electrogenic pumps are primary active transporters
that hydrolyze ATP and use the energy released from ATP
hydrolysis to transport ions across biological membranes
leading to the translocation of net charge across the
membrane. *(Common board Question)
• - Via ATP hydrolysis (facilitates
3Na+ out: 2K+ in) which gives a
net negative effect continuous
pumping of three sodium ions to
the outside for each two potassium
ions pumped to the inside of the
membrane.
•- maintenance of the
membrane potential by
maintaining the normal
intracellular K+ (150 mM)
and Na+ (10 mM)
concentrations.
• - The fact that more sodium ions are
being pumped to the outside than
potassium to the inside causes continual
loss of positive charges from inside the
membrane; this creates an additional
degree of negativity (about -4 millivolts
additional) on the inside beyond that
which can be accounted for by diffusion
alone.
What would happen if the Na K ATPase
pump malfunctions?

- Cell bursts (Cytolysis)

•1. The resting membrane
potential exists across
the plasma membrane of
all cells.
• 2. It is established and
maintained mostly by K+ leak
channels and to a lesser extent
by the Na + -K + pump, which
actively transports three Na +
ions out of the cell in exchange
for two K +ions.
• 3. It requires asymmetric ionic distribution
across the membrane (i.e., a
concentration gradient of ions (Na+, K+)
and selective permeability through ion
channels (K+ channels and Na+
channels).
• The later is secured because the K +
concentration is 20-fold higher inside
neurons than outside, whereas the Na +
concentration is 10-fold higher outside
than inside.
• 4. Because the plasma
membrane is more permeable
to K + than to other ions, K +
ions tend to leak out until the
accumulated positive charge
outside the cell inhibits further
K + movement.
• 5. The resting potential exists
when there is no net movement
of K + ions (i.e., when outward
diffusion of K + ions is just
balanced by the external
positive charge acting against
further diffusion).
• 6. In this state of equilibrium,
the inside of the cell is
negatively charged relative to
the outside; this potential
difference (voltage) across the
membrane is the resting
membrane potential.
•7. Energy-requiring pumps
in the plasma membrane
help maintain the resting
potential, keeping the cell
(neuron) ready to receive
and transmit signals.
•8. The best known pump is
Na + /K + -ATPase, which
exchanges internal Na + for
escaped K + when ATP is
available.
Membrane Potential Shift are
described :
• Depolarization: A shift in membrane
potential in the positive direction. (-50)
MV

• Hyperpolarization: A change in the

membrane potential that makes the
inside of the membrane even more
negative than it is at rest. (-85mV)
3 types of protein in the axon
membrane:
•1. Leak channels ( passive
channels)
•2. Sodium- potassium pump
•3. Gated channels
2 types of gated channels: (!)

• Chemically- gated ion

channels Voltage- gated ion
channel.

• Voltage- gated ion channel-

along axon.
Voltage- gated

• Na+ channels
• K+ channels

• - open & close in response to specific changes in the

membrane potential.
• - most gated channels are closed at the resting potential.
Sodium (Na+) Channel

• - This has two types of gates:

• - M gates- Activation gate MA 3
• - H gate- Inactivation gate HI 1
• - Each channel contains three
activation (m) gates and one
inactivation (h) gate
The Figure illustrates the Hodgkin-Huxley
model for a single voltage-sensitive sodium
channel:
Potassium (K+) Channel

• - This has only one typ of gate.

• - N gates – Activation gate
• - Each channel contains four
(n) activation gates
Figure: The Hodgkin and Huxley model of the
voltage-sensitive Potassium channel.
Local Potential (Sub- threshold)
• Transient shift of membrane potential in a
localized cell area.
Characteristic
s of Local
Potential
•1. Localized within
a cell area
•2. Graded response
•- Amplitude of the
local potential is
proportional to
stimulus size.
•3. Decrementaly
transmitted
•-Magnitude of charge
decreases the farther it
travels
•4. Potential for
summation
•-Local potential
charges can be "added
up"
•5. Very Rapid
•-Faster than Action
Potential
•-Develops and subsides
over a few milliseconds.
2 Types of local Potential:
LOCAL CHANGE IN PERMEABILITY OF MEMBRANE TO
IONS
• 1. Synaptic potential
• - Receptor ligand binding in post-synaptic membrane
• - This causes conformational change in membrane which
allows selective entrance/ exit of ions
• - Can either be EPSP or IPSP
•2. Generator Potential
• - Potential that occurs in sensory
organs
• - Stimuli induces the potentials
(ex. Light to retina, surface of
object to skin)
CHANGE IN VOLTAGE OR CURRENT

• 1. Electronic potentials (Passive

Conduction)
• - No change in permeability
• - Occurs along the axon as the action
potential travels along it
• - Does not spread far
Postsynaptic Potentials
• Excitatory postsynaptic potential (EPSP) (!)
• - When depolarization occurs, the response is
stimulatory
• - Depolarization might reach threshold,
thereby producing an action potential and a
response from the cell.
• - Neurons releasing neurotransmitter
substances that cause EPSPs are excitatory
neurons.
• - An EPSP occurs because of an increase in
the permeability of the membrane to Na.
Inhibitory postsynaptic potential (IPSP
• - Hyperalization and response inhibitory
• - Decrease action potentials by moving the membrane
potential farther from threshold.
• - Neurons releasing neurotransmitter substances that
cause IPSPs are inhibitory neurons.
• - The IPSP is the result of an increase in the permeability
of the plasma membrane to Cl or K.
How are PSP generated?
• In EPSP:
•1. An action potential
(orange arrow) arrives at
the presynaptic terminal
and causes voltage-gated
Ca2+ channels in the
presynaptic membrane to
open.
•2. Calcium ions enter the
presynaptic terminal and
initiate the release of the
neurotransmitter
acetylcholine (ACh) from
synaptic vesicles.
•3. ACh is
released into the
synaptic cleft by
exocytosis.
•4. ACh diffuses across
the synaptic cleft and
binds to ligand-gated
Na+ channels on the
postsynaptic membrane.
• 5. Ligand-gated Na+ channels
open and Na+ enter the
postsynaptic cell, causing the
postsynaptic membrane to
depolarize. If depolarization
passes threshold, an action
potential is generated along the
postsynaptic membrane.
•6. ACh unbinds from
the ligand-gated Na+
channels, which then
close.
• 7. The enzyme
acetylcholinesterase, which
is attached to the
postsynaptic membrane,
removes acetylcholine from
the synaptic cleft by breaking it
down into acetic acid and
choline.
•8. Choline is symported
with Na+ into the
presynaptic terminal,
where it can be recycled to
make ACh. Acetic acid
diffuses away from the
synaptic cleft.
• 9. ACh is formed within the
presynaptic terminal using
acetic acid generated from
metabolism and from choline
recycled from the synaptic cleft.
ACh is then taken up by
synaptic vesicles.
IN IPSP:
1. Gaba is released and binds to the
gaba receptors in the post synaptic
membrane, it opens Cl Channels and
CL enters the postsynaptic membrane.
Cl is negatively charged, therefore,
post synaptic membrane becomes
hyperpolarized. This does not lead to
action potential. Therefore, it is
Inhibitory.
• Summation
• Local potentials can be added up to reach the threshold and
generate an action potential.
• Local potential + Local Potential = ACTION POTENTIAL

• Threshold potential - is the membrane potential to

which the membrane must be depolarized to initiate
action potential.
Temporal summation
• - a single synapse generates
EPSPs so quickly that each is
generated before the previous one
fades.
• -Allows EPSPs to add up over
time to a threshold voltage that
triggers an action potential
Spatial summation
• -EPSPs from several different
synapses add up to threshold at an
axon hillock.
• -Several synapses admit enough Na+
to reach threshold
• -Presynaptic neurons cooperate to
induce the postsynaptic neuron to fire.
• What causes an action Potential?
• - a Stimulus

• Does any stimulation result in an action potential?

• - NO! The membrane potential must reach the threshold
of excitation. Threshold of excitation is -40mV.
Presynaptic Inhibition

- one neuron suppresses

another the opposite of
facilitation reduces or halts
unwanted synaptic
transmission.
Presynaptic Facilitation

- one neuron enhances

the effect of another one
often combined effort of
several neurons.
Action Potential

• - Fleeting, self-renewing wave of

depolarization (positive wave) that
propagates without decrement along the
entire length of a nerve axon at high
speed. (!)
• - Action potential is transmitted from end
to end.
• - AP generated at the beginning is not
the same as the AP at the terminal end.
Threshold for Initiation of the Action
Potential
• - An action potential will not occur until the initial rise in membrane
potential is great enough to create the positive feedback .
• - Occurs when the number of Na+ ions entering the fiber becomes
greater than the number of K+ ions leaving the fiber. A sudden rise in
membrane potential of 15 to 30mV is usually required.
• - Sudden increase in the membrane potential in a large nerve fiber from -
90mV up to about -65mV usually causes the explosive development of
an action potential. This level of -65mV is said to be the threshold for
stimulation.
• • full-pledged AP produced once
threshold intensity is reached
• • further increase in intensity of
stimulus does not produce increment
or other change in AP
• • constant amplitude and form
• • no AP if stimulus is subthreshold in
magnitude
How is an Action Potential Generated?

•By a sudden brief

increase in the
permeability of the axon
membrane to Na+ which
enters the axon.
Sodium threshold:
• • At rest: the activation gate is closed
• • At threshold level: a sudden conformational change in the activation
gate causes it to open
• – Na permeability increases to 500 fold
• – Na influx will occur
• • when reaching +35, inactivation gate closes
• – Na influx stops
• • Inactivation gate will not reopen until resting membrane potential is
reached
• activation variable for the m-gates is known as m, and the activation
variable of the h-gates is known as h
Potassium Threshold:
• - At rest: K channel is closed
• – At +35mV
• • K channel open up slowly
• • This slow activation causes K efflux
• – After reaching the resting still slow K channels may remain
open: causing further hyperpolarisation

• Spike Potential: Rapid rise and fall of membrane potential

Summary of Action Potential:
Refractory Period
• - Required so that a neuron can get another action
potential.
• - Prevents the action potential from moving in both
directions on axon
• - Sets an upper limit to frequency of action potentials.
• - Is a period during which a nerve or muscle is incapable
of responding to stimulation, especially following a
previous stimulation
• 2 Types : (!)
• Absolute RP
• total inability to respond
• All Na+ channels are open thus no new AP is produced, even with
increased stimuli (Absolute Refractory period)
• Starts from threshold to 1/3 of repolarization

• Threshold to Peak (A-B)

• Na+ channels close gradually after 1ms
• K+ ions continue to efflux
• 9 DREAMCATCHERS “Success is not final, failure is not fatal; it is the courage to
continue that counts.” – Winston Churchill
• Peak to 1/3 of Repolarization (B-C)
• Na+ channels remain closed because the activationgate "plugs" each channel
• No way to activate Na+ channels

• During The Absolute Refractory period:

• - The axon membrane cannot respond to a depolarization. Even if the stimulus is
increased.

• WHY?
• - All Na channels are open
• - Na+ voltage gates are closed and inactivated
• Relative RP
• There is a response to very strong stimuli
• During this period nerve membrane can be excited by
supra threshold stimuli
• At the end of repolarisation phase inactivation gate
opens and activation gate closes
• This can be opened by greater stimuli strength
Duration of ABSOLUTE AND
REFRACTORY period
What Restores concentrations of the
Ions?
•The sodium and
potassium pump restores
the resting period
concentrations of the
sodium and potassium
ions.
CLINICAL CORRELAT
HYPOKALEMIA (LOW K+ )

• -May be caused by K+ accumulation

in the muscles
• - Decrease K+: Resting membrane
potential
• - Hyperpolarized, slow to reach
threshold
• - Results in weakness and eventual
paralysis (Hypokalemic periodic
paralysis)
HYPONATREMIA (LOW Na+)

• - Decreased ability to activate Action Potential

• - Signaling decreases
• - Results in depression of sensorium (senses) and
stupor
• - No sodium, no action potential
ACTION POTENTIAL
GENERATION
• The action potential is generated at the axon hillock,
where the density of voltage-gated sodium channels is
greatest.
• The action potential begins when signals from the
dendrites and cell body reach the axon hillock and cause
the membrane potential there to become more positive,
a process called depolarization.
ACTION POTENTIAL PROPAGATION
DIRECTION
Direction of AP (Action Potential) is
usually Orthodromic
• Axodendritic Synapse – an axon synapses with a
dendrite of a succeeding neuron.
• Axoaxonic Synapse – an axon synapses with another axon
• When an action potential is initiated in the middle of it, two impulses
traveling in opposite directions are set up by electrotonic
depolarization on either side of the initial current sink.
• Conduction in the opposite direction is called antidromic. Because
synapses, unlike axons, permit conduction in one direction only, an
antidromic impulse will fail to pass the first synapse they encounter
and die out at that point.

• In physiology, it will not be able to move forward because the synapse in

the axon will not work in reverse.
• - Positive charges from the membrane ahead of and behind the
action potential flow into the area of negativity represented by
the action potential ("current sink").
• - The negative charge outside of the cell attracts positive
charges at the next segment of the axon and is drawn toward
the area of negativity. Thus, enhancing propagation of impulse
across.
• - Electrotonic potential
ACTION POTENTIAL TRAVEL IN ONLY ONE
DIRECTION: TOWARD THE SYNAPTIC
TERMINALS. WHY?
• - Inactivated Na+ channels behind the zone of
depolarization prevent the action potential from traveling
backwards
SALTATORY CONDUCTION: Action
Potential seems to JUMP
• • Myelinated regions of axon are electrically insulated
• • Electrical charge moves along the axon rather than
across the membrane
• • Action potentials occur only at unmyelinated region
• o Happens in the Nodes of Ranvier
• Voltage gates occur at these nodes
• *APs do NOT decrease in AMPLITUDE asa they are
conducted
IMPULSE TRANSMISSION CAN BE
SPED UP BY:
1. Increasing the diameter of the axon
• - increase in diameter → decrease cytoplasmic resistance
→ increase flow of ions
• *For example, an alpha motor neuron which conducts motor impulses coming
from the brain going to the muscle is large in diameter compared to a C fiber. So
between these 2, there is faster transmission of impulse in alpha neurons.
• *There are 2 fibers that conduct pain: Alpha delta and C fibers.
• - between these 2, alpha is stil faster because it is larger in diameter.
2. Presence of myelin sheath
• since the intervening parts of the axon membrane do not have
to be successively depolarised it takes less time for the action
potentials to pass from node to node
• • this results in nerve impulse transmission that is much faster,
• • the consequence of which is that smaller myelinated nerves
can transmit impulses much faster than larger non-myelinated
ones which alleviates the ‘packing problem’.
3.Temperature
• Temperature affects the:
• 1. Rate of diffusion
• 2. Rate of energy release by respiration for active
transport (since it is controlled by enzymes)

• *In endothermic animals (those who maintain a high

body temperature), nerve impulse transmission is faster
SYNAPSE
• - The term synapse was introduced at the beginning of the twentieth
century by Charles Sherrington to describe the specialized zone of
contact at which one neuron communicates with another. This
site had first been described histologically at the level of light
microscopy by Ramón y Cajal in the late 19th century.
• - The average neuron forms several thousand synaptic connections
and receives a similar number. It is a junction between two cells, is
the site where action potentials in one cell can cause the
production of action potentials in another cell
Types of synapses
• Based on location
• CENTRAL VS PERIPHERAL
• - Central synapse forms the connections between different neurons in
the central nervous system (CNS) and is generally regarded as
functionally more complex than the NMJ (neuromuscular junction).
• - Peripheral synapse is a synapse that is located outside of the central
nervous system.

• An example of a peripheral synapse is the neuromuscular junction where

axons of motoneurons synapse with muscle fibers. Another example is
the myenteric plexus of the enteric nervous system.
Gray’s Classification of Central Synapses
• *Gray classified two types of synapses within the brain
based on the ultrastructural characteristics of the
presynaptic (vesicle-bearing) and postsynaptic partners
(length of apposed membrane, membrane thickenings
and synap tic cleft):
• Gray's Type 1 Synapse

– Asymmetric Synapse
• • Round or spherical vesicles
• • Thickened post synaptic density
• – Excitatory
• – Found on dendritic spines and dendrite shafts.
• – Spherical appearance of the synaptic vesicles within the
axonal bouton.
Gray's Type 2 Synapse

– Symmetric Synapse
• • Flattened or elongated presynaptic vescles
• • No prominent post synaptic density
• - Inhibitory (no action potential, leads to hyperpolarization)
• - flattened appearance of the synaptic vesicles within the
axonal bouton.
• - occurred primarily on dendrite shafts and neuronal cell
bodies.
• *2 ions that are affected in the presence of inhibitory
potential are Chloride and Potassium
• - Chloride enters the cell and contributes to the negativity
• - Potassium exits the cell, carrying its positive charge
• *The sterotypical and most abundant synapse in the
central nervous system is the asymmetric synapse
occurring between an axon and a dendritic spine
• Based on method of signal transmission
ELECTRICAL VS CHEMICAL
SYNAPSE
• * The War of the Soups (Chemical) and the Sparks
(Electrical) in the early 1900’s
• Major proponents:
• Chemical: Sir Henry Dale & Otto Loewi
• Electrical: Sir John Eccles
• *Before, chemical won. Proved with an experiment. But
later it was also proved that is was also electrical.
*Sir J.C. Eccles
• Australian (one of Sherrington’s last students) - 1st an
electrical impulse passed directly from the presynaptic
axon to postsynaptic cell then a more prolonged action of
Neurotransmitter
*Otto Loewi
• German - He dissected out of frogs two beating hearts: one with the
vagus nerve which controls heart rate attached, the other heart on its
own. Both hearts were bathed in a saline solution (i.e. Ringer's
solution). By electrically stimulating the vagus nerve, Loewi made the
first heart beat slower. Then, Loewi took some of the liquid bathing
the first heart and applied it to the second heart. The application of the
liquid made the second heart also beat slower, proving that some
soluble chemical released by the vagus nerve was controlling the
heart rate. He called the unknown chemical Vagusstoff. It was later
found that this chemical corresponded to Acetylcholine
*Henry Dale
• British - Although Dale and his colleagues first identified
acetylcholine in 1914 as a possible neurotransmitter,
Loewi showed its importance in the nervous system. The
two men shared the 1936 Nobel Prize for Medicine.
• Dale also originated the scheme used to differentiate neurons according to the
neurotransmitters they release. Thus, neurons releasing noradrenaline (known in
the United States as norepinephrine) are called noradrenergic, neurons releasing
GABA are GABAergic, and so on. This is called Dale's principle (sometimes
erroneously referred to as Dale's Law), one interpretation of which holds that
each neuron releases only one type of neurotransmitter.
• This particular interpretation of Dale's principle has been shown to be false, as
many neurons release neuropeptides and amino acids in addition to classical
neurotransmitters such as acetylcholine or biogenic amines (see cotransmission)
(Bear, et al. 2001). This finding, that numerous neurotransmtters can be released
by the same neuron, is referred to as the "coexistence principle." This
phenomenon was most popularized by the Swedish neuroanatomist and
neuropharmacologist Tomas Hökfelt, who is considered to be the "Father of
the Coexistence Principle.“
Location of Electrical Synapses

• Hippocampus
• Inferior olive
• Locus coeruleus
• Hypothalamus
• Spinal cord
• Olfactory bulb
• Retina
• * A number of reports have appeared over the years,
describing the presence of gap junctions and the
expression of distinct connexins in different regions of the
adult mammalian brain, such as the hippocampus, inferior
olive, locus coeruleus, hypothalamus, spinal cord, and
olfactory bulb
ELECTRICAL SYNAPSE VS
CHEMICAL SYNAPSE

*Study this table

How will an electrical signal pass from one
cell to another?
- Through its arrangement. It
rotates clockwise. It opens up a
channel or a pore inside.
• *Study this table
• * At chemical synapses the presynaptic and postsynaptic
neurons are completely separated by a small space, called the
synaptic cleft; there is no continuity between the cytoplasm of
one cell and the next.
• In contrast, at electrical synapses the pre- and postsynaptic
cells communicate through special channels, the gap-junction
channels, that directly connect the cytoplasm of the two cells.
• The connexins are arranged in such a way that a
pore is formed in the center of the structure. The
resulting connexon, with a pore diameter of
approximately 1.5 to 2 nm, has a characteristic
hexagonal outline, as shown in part A. In some gap-
junction channels the pore is opened when the
subunits rotate approximately 0.9 nm at the
cytoplasmic base in a clockwise direction.
• - The most important difference can be observed by
injecting a positive current into the presynaptic cell to elicit
a depolarization. At both types of synapses outward
current across the presynaptic cell membrane deposits
positive charge on the inside of the presynaptic cell
membrane, thereby depolarizing the cell.
• At an electrical synapse some current injected into the
presynaptic cell escapes through resting (nongated) ion
channels in the cell membrane. However, some current also
enters the postsynaptic cell through gap-junction channels that
connect the cytoplasm of the pre- and postsynaptic cells and
that provide a low-resistance (high-conductance) pathway for
electrical current.
• - At chemical synapses all current injected into the presynaptic
cell escapes into the extracellular “fluid. However, the resulting
depolarization of the presynaptic cell membrane can produce
an action potential that causes the release of neurotransmitter
molecules that bind receptors on the postsynaptic cell. This
binding opens ion channels that initiate a change in membrane
potential in the postsynaptic cell.
THE STRUCTURE OF ELECTRICAL
SYNAPSES
- Electrical synapses are direct
cytoplasmic connections
between two nerve cells,
through channels called gap
junctions. Electrical synapses
are often "rectifying" which
means that they allow electrical
charge
• A. The electrical synapse, or gap
junction, is composed of
numerous specialized channels
that span the membranes of two
neurons. These gap-junction
channels allow current to pass
directly from one cell to the other.
•B. A gap-junction channel is
actually a pair of
hemichannels, one in each
apposite cell that connects
the cytoplasm of the two
cells.
• C. Each hemichannel, or connexon, is
made up of six identical subunits
called connexins. Each connexin is
approximately 7.5 nm long and spans
the cell membrane. A single connexin
has intracellular N- and C-termini,
including a short intracellular N-
terminal #-helix (NTH), and four
membrane-spanning
#-helixes (1–4). There are regions of similarity in the amino acid sequences of
gap-junction proteins from many different kinds of tissue. These include the
transmembrane helixes and the extracellular regions, which are involved in the
homophilic matching of apposite hemichannels.
THE STRUCTURE OF CHEMICAL
SYNAPSES
• - synaptic knob of presynaptic neuron contains synaptic
vesicles containing neurotransmitter
• - many docked on release sites on plasma membrane
• - ready to release neurotransmitter on demand
• - a reserve pool of synaptic vesicles located further away from
membrane postsynaptic neuron membrane contains proteins
that function as receptors and ligand-regulated ion gates
CATEGORIES OF CHEMICAL
TRANSMISSION BETWEEN NERVE
CELLS
• - About half of the fast synapses in the brain are excitatory, and most of
these fast excitatory synapses use glutamate as their neurotransmitter.
• - The other half of the fast synapses are inhibitory, and most of these fast
inhibitory synapses use GABA as their neurotransmitter.
• - Synaptic transmission at fast synapses occurs in less than
• 1/1OOO of a second and is attributable to the ability of the fast-acting
neurotransmitters to open ligand-operated ion channels present in the
plasma membrane of the postsynaptic cells.
• - In fast excitatory transmission, glutamate binds to a receptor,
causing a change in the conformation of the receptor, which allows
positively charged sodium ions to rush into the cell and causes a
depolarizing (that is, excitatory) signal to be generated in the target
cell.
• - In fast inhibitory transmission, GABA binds to its receptor, causing a
change in the conformation of the receptor, which allows negatively
charged chloride ions to permeate the cell and causes a
hyperpolarizing (that is, inhibitory) signal to be generated in the
targetcell.
FAST CHEMICAL SYNAPSES

• - Fast chemical synapses release a neurotransmitter substance that

binds directly to ion channels on the postsynaptic membrane and
changes the permeability of the postsynaptic membrane, thus causing
an electrical potential change
A. Presynaptic terminal
• - Motor neuron of the neuromuscular junction.
• - Contains the neurotransmitter agent (NTA) – Acetylcholine
(Ach)
• - Release of Ach is stimulus-secretion coupling (with calcium)
• - Entry of calcium in the terminal endings of the neuron triggers
the fusion of SNAREs.
• The vesicular SNARE (Synaptobrevin) fuses with the
membrane SNAREs ( Syntaxin and SNAP 25) to cause
exocytosis of acetylcholine.
• - The release of NTA, acetylcholine in the neuromuscular
junction is quantal. It means it is enough to cause action
potential following a local potential known as end plate
potential.
B. Synaptic cleft
• - Divided into a primary and a secondary cleft
• 1. Primary cleft
• - Space that separates the presynaptic membrane of the
neuron’s terminal ending and the postsynaptic membrane
of the sarcolemma.
• - Has no lateral boundaries and communicates with the
extracellular space
• 2. Secondary cleft
• - Space between the junctional folds of the postsynaptic
membrane
• - Communicates with the primary clefts
• - Has high concentration of acetylcholinesterase, an
enzyme that degrades Ach.
C. Postsynaptic terminal
• - The plasmalemma of the skeletal muscle opposite the nerve
terminal at the neuromuscular junction
• - The normal junctional fold has a slender stalk and a terminal
expansion (peak).
• - Ach receptors are highly concentrated in the peaks of the fold

• Release of Ach is quantal from the neuron that causes

summation of end plate potential to action potential.
• - Action potential is propagated in the entire plasmalemma till the
transverse tubule (Ttubule)
• - Opening of the voltage-gated calcium channel (DHP receptors) in the
Ttubule that causes calcium influx that does not proceed to the
sarcoplasm instead will excite the Ryanodine (RYR) receptors in the
cisterns of sarcoplasmic reticulum.
• - RYR is a calcium-gated calcium channel.
• - Release of calcium from the cisterns into the sarcoplasm
• - Calcium binds to Troponin C. Tropomyosin is displaced from covering
the myosin binding sites in actin.
• - Conformational change occurs causing exposure of myosin binding
sites on actin
• - Myosin heads binds to actin
• - Presence of ATP will partly detach Myosin heads from actin.
Hydrolysis of ATP will power the ricocheting of the myosin
heads (“Power stroke”) resulting in transfer of myosin heads to
the other actin binding sites (Sliding Filament Theory).
• - Process continues until action potential ceases or after
calcium are no longer available for binding with Troponin C.
SLOW CHEMICAL SYNAPSES
• *Slow because the end product would be generation of
second messengers
• 16 DREAMCATCHERS “Success is not final, failure is not fatal; it is the courage
to continue that counts.” – Winston Churchill

• - For slow chemical synapses, the neurotransmitter substance binds to a receptor

protein on the postsynaptic membrane. This binding causes release of an
intracellular transmitter in the postsynaptic cell and that transmitter then binds to
ion channels on the postsynaptic membrane.
• - Slow responses act by triggering biochemical changes through G protein-linked
receptors. These are called metabotropic receptors. The G protein may either be
directly coupled to an ion channel or may trigger the activation or inhibition
through a secondary messenger system. The duration of the response may range
from msec to hours.
• - The G protein may either be directly coupled to an
ion channel or may trigger the activation or inhibition
through a secondary messenger system. The
duration of the response may range from msec to
hours.
NEUROTRANSMITTERS

•- substances that
mediate chemical
signalling between
neurons.
Criteria That Define a Neurotransmitter
• The substance must be present within the presynaptic
neuron.
• The substance must be released in response to
presynaptic depolarization, and the release must be
Ca2+dependent.
• Specific receptors for the substance must be present on
the postsynaptic cell.
MAJOR EXCITATORY
NEUROTRANSMITTER
•Glutamate - the principle
excitatory neurotransmitter
in the brain and it is
estimated that over half of all
brain synapses release this
agent.
• - Glutamate-glutamine cycle
• - Glutamate is a non essential AA that does not cross the blood
brain barrier and therefore must be synthesized in neurons from
local precursors. The most prevalent precursor for glutamate
synthesis is glutamine. Which is released by glial cells.
• - Once released glutamine is taken up into the presynaptic
terminals and metabolized to glutamate by the glutaminase.
• - Glutamate is packaged into synaptic vesicles by transporters
termed vesicular glutamate transporter (VGLUT).
• - Once released glutamate binds to glutamate receptors on the
post synaptic cell. The glutamate is removed from the synaptic
cleft by the excitatory amino acid transporters (EAAT’s)
• - Glutamate (excess) taken up by glial cells is converted
into glutamine by glutamine synthetase. Glutamine is then
transported out of the glial cells and into the nerve
terminals.
• There are two types of glutamate receptors: Ionotropic
and Metabotropic.
• The iontropic receptors are:
• NMDA – N methyl D Aspartate
• AMPA – Alpha amino 3 hydroxyl 5 methyl 4 isoxazole
proprionate
Kainate

• *All of the ionotropic glutamate receptors are non

selective cation channels
• *They allow the passage of Na and K and small amounts
of Ca thus producing EPSP.
• 3 unique characteristics of the NMDA receptors:
• 1. When glutamate binds to receptor, to cause
depolarization, sodium usually enters BUT in NMDA
receptors, passage of Calcium also occurs.
• 2. Central opening is blocked by Magnesium.
• 3. Presence of obligatory coagonist (Glycine).
MAJOR INHIBITORY
NEUROTRANSMITTER
• GABA (gamma-aminobutyric
acid) - is secreted by nerve
terminals in the spinal cord,
cerebellum, basal ganglia, and
many areas of the cortex. It is
believed always to cause
inhibition.
• a | Schematic diagram of the synthesis and transport of
GABA (-aminobutyric acid) at synapses.
• GABA is synthesized in inhibitory neurons from glutamate
by the enzyme glutamic acid decarboxylase (GAD), and is
transported into vesicles by a vesicular GABA transporter
(VGAT).
• GABA can be released either vesicularly or non-
vesicularly (by reverse transport). GABA receptors are
located at pre- and postsynaptic sites. GABAB receptors
are metabotropic receptors that cause presynaptic
inhibition by suppressing calcium influx and reducing
transmitter release, and achieve postsynaptic
inhibition by activating potassium currents that
hyperpolarize the cell.
• Reuptake of GABA by surrounding neurons and glia occurs
through the activity of GABA transporters (GAT). Subsequently,
GABA is metabolized by a transamination reaction that is
catalysed by GABA transaminase (GABA-T). The metabolism
of GABA occurs in both neurons (not shown) and glia.
• In neurons and astrocytes, GABA is degraded by GABA
transaminase (GABAT) to succinic semialdehyde (SSA).
TABLE FOR
NEUROTRANSMITTERS
Preventing Stroke Damage
• Glutamate is an important excitatory neurotransmitter in the
brain and spinal cord. During a stroke, oxygen-deprived
presynaptic neurons release large amounts of glutamate.
Glutamate binds to postsynaptic neurons and stimulates them
to release nitric oxide (NO), which in high concentrations can
be toxic to cells.
• The NO diffuses from the postsynaptic neurons and causes
damage to surrounding cells.
• It’s possible that stroke damage may be reduced by
drugs, not yet developed, that block glutamate receptors
or inhibit the production of NO.
• Serotonin acts as an inhibitor of pain pathways in the
cord, and an inhibitor action in the higher regions of the
nervous system is believed to help control the mood of
the person, perhaps even to cause sleep.
Norepinephrine
• is secreted by the terminals of many neurons whose cell bodies are
located in the brain stem and hypothalamus. Specifically,
norepinephrine-secreting neurons located in the locus ceruleus in the
pons send nerve fibers to widespread areas of the brain to help
control overall activity and mood of the mind, such as increasing the
level of wakefulness. In most of these areas, norepinephrine probably
activates excitatory receptors, but in a few areas, it activates inhibitory
receptors instead. Norepinephrine is also secreted by most
postganglionic neurons of the sympathetic nervous system, where it
excites some organs but inhibits others.