Introduction to Neurophysiology

Introduction
Neurophysiology is the branch of physiology dealing with the
functions of the nervous system. ie The study of the functional
properties of neurone s, glia, and networks.

 Historically it has been dominated by electrophysiology—the

electrical recording of neuronal events ranging from the molar (the
electroencephalogram, EEG) to the cellular (intracellular recording
of the properties of single neurons).
 As the neuron is an electrochemical machine, it is impossible to
separate electrical events from the biochemical and molecular
processes that bring them about.
 Neurophysiologists today use techniques from chemistry
(calcium imaging), physics (functional magnetic resonance
imaging, fMRI), and molecular biology (site directed mutations) to
study brain function.
Below you will learn all about

 Ion Channels
 Resting Membrane and Action Potential
 Neuromuscular Junction / Synapses
 Nerve Conduction
 Neurotransmitters, Receptors and Pathways
Ion Channels
An ion channel is a protein macromolecule that crosses the breadth of
a membrane and allows molecules to pass through. The ions move in a
direction determined by the electrochemical gradient across the
membrane.

 Ions tend to flow from an area of high concentration to an area

of low concentration.
 In the presence of a voltage gradient, there may be no flow of
ions despite unequal concentrations.
 Ion channels can be open or closed.
 Opening is brought about by changing the voltage across the
membrane, or binding a chemical substance to a receptor.
 Most important role is that they provide the neuron with
electrical excitability.
 Found in all parts of the neuron and to a lesser extent in the
neuroglial cells.

Types of Channel

1. Voltage Gated
2. Chemically Activated
3. Mechanical Stretch/Pressure.
Fundamental Properties of an Ion Channel

1. It is made up of a number of protein sub units, sitting across the

membrane, allowing ions to cross from one side to the other.
(Transmembrane pore)
2. The channel must be able to move from open to closed state, and
back.
3. Must be able to open in response to the appropriate stimuli.
Some channels respond to chemical stimulus (particularly at the
synapse). These channels have specific receptors for that chemical,
that leads to channel opening.

Resting Membrane and Action Potential

 In the resting state, the neuronal cell membrane is fairly

impermeable to ions. This is crucial for the generation of
the resting membrane potential. 
 The major intracellular ion is Potassium (It is sodium in the
extracellular fluid).
 The natural flow of ions by way of their concentration gradients
is for K+ to leave the cell and Na + to enter.
 This movement of ions out of the cell leads to a negative
membrane potential - Hyperpolarisation.
 The opposite is true for a relative influx of ions -
Hypopolarisation. [2]
The resting membrane is relatively impermeable to Na+ ions, while
remaining permeable to K+ ions. So when the membrane is at rest,
there will tend to be an efflux of K+ ions out of the cell, down its
concentration gradient, leaving excess negative charge behind. This
continues until the chemical concentration gradient that is driving out
the K+ from the cell is exactly at the point where it is offset by the
electrical potential difference generated by this efflux. (the membrane
potential) K+ is then drawn back into the cell.

This steady state of the membrane is called the Equilibrium

Potential.

The equation for deriving the equilibrium potential is called

the Nernst equation. 

There is actually a slightly unexpected increased positive charge in

axons due to a small permeability to Na+ ions of the membrane in the
resting state. This is offset by ATP dependent Na+/K+ exchange
pump. I pumps out 3 Na+ ions for every 3K+ ions brought in to the
cell. However, it makes only a tiny contribution to the resting
membrane potential of the cell.
Action Potential

Defined as a "single electrical impulse passing down an axon".

It is all or nothing in its action. This means that once the threshold
stimulus intensity is reached, an action potential will be generated.

Information in the nervous system is coded and interpreted by the

frequency of firing, not by the size of action potential.

Threshold Stimulus Intensity: The value at which the net inward

current(determined by Na+ ions) is just greater than the net outward
current (carried by K+ ions). It is normally -55mV (critical firing
threshold)

The AP most readily occurs at the axon hillock because this is where
there is a greater density of Na+ ion channels. It is for this reason that
this is the site of AP initiation in the neuron.

If the threshold is not reached, the action potential will not be

generated, and transmission of the signal is terminated at that point. 

Sequence of events for an Action Potential to be generated

1. Depolorising voltage activates the voltage sensitive Na+ ion

channels in the neuronal membrane: Na+ ions flow down the
electrochemical gradient. Membrane is depolarised further.
Further Na+ channels open in aPositive feedback loop.
When there is a greater inward current of sodium ions
compared to the efflux of K+ ions, there is fast opening of all
 Na+ channels. This depolarises the membrane towards the
equilibrium potential for Na+(+55mV). Spike of AP is
generated, but fails to reach equilibrium. potential for Na+ due
to the increasing K+ efflux.
2. As the Na+ channels become less active the AP falls. This
inactivation is voltage dependent. During the falling phase the
K+ current is important as it leads to a short period of
membrane hyperpolarisation before it deactivates.
3. Membrane potential returns to the resting state.

Neuromuscular Junction / Synapses

Synapse

A synapse is the junction of two neurons. The chemical synapse is the

predominate one found in the nervous system, however electrical
synapses are found in cardiac muscle and glial cells.
Synaptic Transmission

 Action potential arrives, leads to depolarisation of the

presynaptic terminal. Voltage dependent Ca2+ channels open in
the active zones of the terminal. This leads to influx of Ca2+.
 Influx of Ca2+ leads to phosphorylation and alteration of
amount of presynaptic calcium binding proteins. This liberates the
vesicle from its presynaptic actin network, It then binds to the
presynaptic membrane.
 The fusion of the vesicle to the membrane leads to the formation
of a small channel, which quickly expands and releases its contents
into the synaptic cleft. The vesicle membrane is recycled by
endocytosis.
 Released neurotransmitter diffuses across synaptic cleft with the
goal of binding to the postsynaptic receptor.
 Activation of the postsynaptic receptor leads to a change in the
postsynaptic membrane potential.
 There are alternative theories that suggest that the
neurotransmitter is delivered via molecules or membrane channels
rather than vesicles.

Nerve Conduction
Action potential propagation is achieved by local current spread.

The nerve is insulated with myelin if its size is above a certain

diameter, with the Nodes of Ranvier at various intervals along its
length.
Unmyelinated Axons

Action potential  leads to depolarisation of the membrane

immediately in front (and behind). The membrane is in a refractory
state, so the action potential is only conducted in 1 direction. This is
feasible in small axons, but the spread of current is slow.

Myelinated Axons

Same sequence of events as in the unmyelinated axons. There is

however a significant difference. The progressing action potential
encounters high resistance, low-capacitance structure - myelin
wrapped around the axon. The depolarising current passes along the
axoplasm, until it reaches the low resistance Node of Ranvier with its
large amount of Na+ channels. The action potential is then generated
at this site. Action potential is conducted from node to node. This is
called Saltatory Conduction.

Advantages of Myelination

1. Allows for rapid conduction of action potential

2. Minimises metabolic demands on the cell.
3. Increases packing capacity of the NS, allowing more fibres to be
crammed into 1 nerve.
Most nerves greater than 1 micron are myelinated.

Disturbances in conduction are normally due to demyelination

pathologies. They include Guillan Barre syndrome and Multiple
sclerosis.
Postsynaptic Integration:

Each central neuron receives many hundreds of synapses. Each of

these inputs is than integrated into a response by that particular
neuron. This involves processing all the inputs that arrive at any one
time. This is called spatial summation. Processing inputs over a set
period of time is called temporal summation. There will be a mix
of excitatory and inhibitory synapses acting at this point.

Excitatory Post-synaptic potentials

 Binding of neurotransmitter leads to opening of ion channels.

 There is cation influx in post-synaptic process
 Depolarisation of the membrane occurs.
 EPSPs depolarisations recorded in the post-synaptic cell to a
particular excitatory stimulus.
 Depolarisations assoc. with EPSPs can go on to trigger APs if
summation occurs at the synapse.
Inhibitory Postsynaptic potentials

 Ion channels allow postsynaptic anion influx when open.

 Hyperpolarisations of the membrane occur due to influx of CL-
and efflux of K+
 important for modulating the neurons response to excitatory
input at the synapse.
 Found in strategically important sites of the neuron such as the
proximal dendrite and soma.
 They have a large influence on the dendritic tree
 Some neurons provide their own inhibitory influence by having
axon collaterals and their own inhibitory interneurons. This is
termed feedback inhibition. Eg. motorneurons and Renshaw cells
in the spinal cord.

Neurotransmitters, Receptors and Pathways

The neurotransmitter is released at the synapse and works with a
specific protein in the postsynaptic membrane called the  receptor.
In some synapses the neurotransmitter may also be found to interact
with a presynaptic autoreceptor. The PSA acts as a regulator of
the amount of transmitter released.

Receptors are normally specific for a particular neurotransmitter.

There are several types of receptor. Co-released neurotransmitters
may regulate the binding of another transmitter.

Receptors for specific neurotransmitters may be either coupled

directly to ion channels or to a membrane enzyme where the binding
of the neurotransmitter to the receptor either opens an ion channel
via an intracellular enzyme cascade or indirectly modulating the
probability of other ion channels opening in response to voltage
changes. (neuromodulation)
Activated receptor can only return to its resting state once the
neurotransmitter is removed by the process of enzymatic hydrolysis
(uptake) into the presynaptic nerve terminal or into the nearby glial
cells.

Desensitisation/Down regulation: A decrease in affinity of the

receptor for the transmitter in the short term, in the longterm, this
leads to a decrease in the number of receptors.

Supersensitivity/Up regulation: An increased affinity of the

receptor for the transmitter in the short term can lead to an increase
in channels in the longterm.

Receptors:

1. Ionotropic: N-methyl-D-aspartate(NMDA)
2. Non NMDA.
3. Metabotropic : G-protein associated glutamate receptors that
respond by initiating intracellular biochemical events,
modulating synaptic transmission.
There are a large number of Neurotransmitters:

1. Excitatory Amino Acids: These are the main excitatory NTs in

the CNS. The main NT in this group is Glutamate which acts at a
number of receptors. 
2. Inhibitory Amino Acids: These are the major inhibitory
neurotransmitters, the main one of which is GABA, present
throughout the CNS. Glycine, found mainly in the spinal cord.
 3. Monoamines: Found in small groups of neurons in the brain
stem, projecting widely into the CNS. Found in the autonomic
NS. They bind to a host of receptors.
4. Acetylcholine: Widely distributed throughout the nervous
system, including the neuromuscular junction and autonomic
NS.
5. Neuropeptides: Found all over the NS. Often released
simultaneously with other NTs.
In addition, over 50 neuroactive peptides have been found, and new
ones are discovered regularly. Many of these are "co-released" along
with a small-molecule transmitter. Nevertheless, in some cases a
peptide is the primary transmitter at a synapse. β-endorphin is a
relatively well known example of a peptide neurotransmitter because
it engages in highly specific interactions with opioid receptors in the
central nervous system.

Single ions (such as synaptically released zinc) are also considered

neurotransmitters by some, as well as some gaseous molecules such as
nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide
(H2S). The gases are produced in the neural cytoplasm and are
immediately diffused through the cell membrane into the extracellular
fluid and into nearby cells to stimulate production of second
messengers. Soluble gas neurotransmitters are difficult to study, as
they act rapidly and are immediately broken down, existing for only a
few seconds.

The most prevalent transmitter is glutamate, which is excitatory at

well over 90% of the synapses in the human brain. The next most
prevalent is Gamma-Aminobutyric Acid, or GABA, which is inhibitory
at more than 90% of the synapses that do not use glutamate. Although
other transmitters are used in fewer synapses, they may be very
important functionally: the great majority of psychoactive drugs exert
their effects by altering the actions of some neurotransmitter systems,
often acting through transmitters other than glutamate or GABA.
Addictive drugs such as cocaine and amphetamines exert their effects
primarily on the dopamine system. The addictive opiate drugs exert
their effects primarily as functional analogs of opioid peptides, which,
in turn, regulate dopamine levels.