CENTRAL NERVOUS SYSTEM: General Principles & Introduction(Guyton & Hall, 13th Edition, Chapter 46)

Dr. Ayisha Qureshi

Professor

MBBS, MPhil

Learning Objectives

• By the end of the lecture, you should be able to:

1. Name the divisions of the nervous system.

2. Name the various parts of a neuron.

3. Explain the physiological basis of Resting Membrane Potential.

4. Name the various phases of an Action Potential and describe their ionic basis.

5. Differentiate between Action and Graded Potential.

6. Explain the mechanism of transmission across a chemical synapse.

7. Enlist and describe the properties of a synapse.

8. Differentiate between neurotransmitters and neuromodulators.

The Brain is the most complex tissue of the body!! It mediates behavior from

simple movements & sensory perceptions to thinking, learning and memory.

Brain’s main function, thinking, is hardly

understood at all.

THE NERVOUS SYSTEM CAN BE DIVIDED INTO

CENTRAL, PERIPHERAL AND AUTONOMIC

NERVOUS SYSTEM.

Nervous System

CENTRAL NERVOUS SYSTEM

Brain Spinal Cord

PERIPHERAL NERVOUS SYSTEM

Sensory Input Motor Output

Autonomic nervous system

What makes up the brain, the spinal

cord and the peripheral nerves?

NEURONS.(In most places, neurons are supported by neuroglia.)

NEURONS HAVE FOUR SPECIALIZED REGIONS:

1. Cell body

2. Dendrites

3. Axon, and

4. Presynaptic terminals

RECALL THE FOLLOWING:

• Structure of a Neuron

• Resting Membrane Potential

• Action Potential

• Synapse

Structure of A Neuron!

The structure of the neuron also determines the

function of the neuron by determining the direction of

flow of information…

This information transmission takes place thru action potentials or

simply “Nerve Impulses”, thru a succession of neurons, one after

another.

The “nerve impulse” may be:

1.Blocked,

2.Changed from a single impulse into repetitive impulses, OR

3.Integrated with impulses from other neurons.

All these functions can be classified as “Integrative functions of

neurons”.

Thru synapses!

How are neurons connected?

SYNAPSE

A synapse is a an area of functional contact & anatomical differentiation between 2 neurons.

• Action potentials cannot travel across the synapse.

• Nerve impulse is carried by neurotransmitters (NT), also called transmitter substance, which transmit the nerve impulse from one nerve cell to the next across the synapse.

• The structure of synapse consists of:

– presynaptic terminal (NT are synthesized & released)

– post synaptic terminal (has neuroreceptors in the membrane)

– synaptic cleft

How many synapses

are in one neuron? 1,000 to 10,000!!

CLASSIFICATION OF

SYNAPSES:

Classification

Chemical synapse

Electrical synapse

Mixed synapse

Physiological/functional

Types of Synapses:

1. Chemical Synapse (transmission thru chemicals i.e. NT)

throughout the CNS

2. Electrical Synapse (Gap Junctions)

B/w the cardiac muscles and b/w visceral smooth muscle

- Impulse conducted without release of NT

- Gap junctions allow free movement of ions

- No synaptic delay

- Unidirectional & Bidirectional conduction

3. Mixed Synapse i.e. having both electrical & chemical regions

Chemical synapses have one important characteristic that

makes them highly desirable for transmitting most nervous

system signals:

Transmission of signals in one direction (from the

presynaptic neuron to the postsynaptic neuron).

This is the principle of one-way conduction at chemical

synapses. It allows signals to be directed towards specific

goals and allows it to perform it’s functions more

effectively.

Dendrites: projecting for at least 1 mm

No. of synaptic knobs forming presynaptic terminals: 10,000 to 200,000

95% synapses on the dendrites

5-20% synapses on the soma

We study a typical anterior motor neuron. Are

the other neurons in the CNS similar to or

different from this neuron? If so, why is this

difference significant?

Neurons in the other parts of the brain differ from the

anterior motor neuron in:

1.The size of the cell body,

2.The length, size and number of dendrites,

3.The length and size of the axons, and

4.The number of presynaptic terminals

These differences make neurons in different parts of

the nervous system react differently to incoming

synaptic signals and, therefore, perform many different

functions.

MECHANISM OF SYNAPTIC

TRANSMISSION

Remember that the terminal has 2 internal structures important to

the synapse:

• The transmitter vesicle

• Mitochondria that provide ATP for transmitter synthesis

Mechanism of Synaptic Transmission:• Action potential reaches the presynaptic terminal

↓

• Voltage-gated Ca2+ channels open

↓

• Influx of Ca2+

↓

• Exocytosis of synaptic vesicles (role of release sites)

↓

• Neurotransmitter (NT) is released into the synaptic cleft and diffuses to the postsynaptic terminal

↓

• NT binds to neuroreceptor on postsynaptic membrane

↓

• Causes either the ion channels to open OR the second messenger system to be activated.

↓

• Graded potential is generated in the postsynaptic neuron

↓

• The NT is degraded by the specific enzymes in the synaptic cleft.

ROLE OF CALCIUM IONS IN EXOCYTOSIS

Ca ions enter the presynaptic terminal

↓

Bind with the RELEASE SITES (special protein molecules present on the inside of the presynaptic membrane)

↓

Release sites open up through the presynaptic membrane

↓

Transmitter vesicles release their NT through these release sites

↓

With each action potential a few vesicles will empty their NT content into the cleft.

(about 2000-10,000 molecules of NT are present in each vesicle)

Fate of Neurotransmitters:

Fate of the Neurotransmitter:

The NT dissociates from the Receptor & can have either of

the 3 fates:

• Enzymatic Degradation: A portion of it is inactivated by

the enzymes present in high concentration at the

postsynaptic membrane.

• Re-uptake of remaining NT by Pre-synaptic neuron and

Re-used.

• Diffusion into the blood stream.

The NT acts on the Receptor proteins present on the

Post-synaptic membrane

The Post-synaptic membrane contains large number of RECEPTOR PROTEINS, which have 2 parts:

1. A binding component (protruding outwards into the synaptic cleft)-this binds the NT coming from the Pre-synpatic terminal.

2. An ionophore component (passing all the way through the membrane to the interior of the post-synaptic neuron).

Receptor activation controls the opening of ion channels in the post-synaptic cell in one of the two ways:

a. By gating Ion Channel directly: that allows passage of specific ions.

OR

a. By activating a Second messenger: that is NOT an ion channels and instead activates one or more substances inside the postsynaptic neuron. These second messengers increase or decrease specific cellular functions.

Many functions of the nervous system, e.g learning & memory, require

prolonged changes in neurons for days to months after the initial transmitter

substance is gone.

The ion channels are not suitable for causing prolonged postsynaptic

neuronal changes because these channels close within milliseconds after

the transmitter substance is no longer present.

Prolonged postsynaptic change is achieved by activating a “second

messenger” chemical system inside the postsynaptic neuronal cell itself.

Why is there a need for a second messenger system

when you already have a very rapid ligand gated ion

channel system present?

Receptor Proteins/ Postsynaptic Receptors

Binding Component

Ionophorecomponent

Ligand gated Ion channel

Cation Channels: Excitatory

Anion Channels: Inhibitory

Second Messenger Activator

Please read the details on page 584, Guyton, (13th Edition)

Why do we have excitatory or inhibitory

receptors when we already have ion channel

or second messenger system for activation?

This gives an additional dimension to nervous

function, allowing restraint/control of nervous

action and excitation.

ELECTRICAL EVENTS DURING

NEURONAL EXCITATION

(as studied in the anterior motor neurons)

Recall resting membrane potential please!

•The question we must answer is:

“How do different postsynaptic receptors lead to

excitation or inhibition of the neuron?”

The 3 states of a neuron & effect of ion movement.

What is electro-tonic

conduction?

It is the direct spread of

electrical current by ion

conduction in the fields of the

dendrites but without generation

of action potentials.

Uniform distribution of electrical potential inside the soma…

• Na+ spreads as a wave of depolarization through the soma cytosol(much like the ripples created by a stone tossed into a pond)- ELECTROTONIC CONDUCTION.

• The interior of the neuronal soma contains a highly conductive electrolyte

solution, the intracellular fluid, and has a large diameter (from 10 to 80 µm).

It causes almost no resistance to conduction of electric current.

• Therefore, any change in potential in any part of the intrasomal fluid causes

an almost exactly equal change in potential in all other points of the soma.

• This is an important principle because it plays a major role in “summation” of

signals entering the neuron from multiple sources.

MEMBRANE POTENTIAL CHANGES

IN THE POSTSYNAPTIC NEURON

Depending upon the type of Graded Potential that is generated

(EPSP or IPSP) by their activation, the Receptor Proteins are

labelled as EXCITATORY OR INHIBITORY in nature.

How do different postsynaptic receptors lead to excitation or

inhibition of the neuron?

(By generation of Graded Potential thru excitation or inhibition.)

EXCITATION

(making the potential less

negative)

• Opening of Na

channels…

• Decreased conduction

thru chloride or potassium

channels or both,

• Increase in the no. of

excitatory membrane

receptors or decrease in

the no. of inhibitory

membrane receptors

INHIBITION

(making the potential more

negative)

• Opening of chloride ion channels…

• Increase in conductance of potassium ions out of the neuron

• Activation of receptor enzymes that inhibit metabolic functions that increase the number of inhibitory membrane receptors or decrease the number of excitatory receptors.

Types of Graded Potential

• Na Influx causes an increased

positivity in the neurons.

• This excitation that leads to

depolarization and is called an

Excitatory Postsynaptic

Potential (EPSP).

IPSP

(Inhibitory Postsynaptic Potential)

• Cl influx or K efflux of causes increased negativity inside the neuron leading to hyperpolarization which is called Inhibitory Postsynaptic Potential (IPSP).

EPSP

(Excitatory Postsynaptic Potential)

If the wave is strong enough, and reaches the axon

hillock then this graded potential will lead to the

generation of the action potential.

If it does not reach the axon hillock, then the graded

potential will automatically die off and NO action

potential will be generated.

Question: The action potential does not occur adjacent

to the excitatory synapses. WHY?

Because the soma has relatively few voltage-gated sodium channels in its

membrane, while the membrane of the initial segment has 7 times the

conc. of these channels and, therefore, can generate an action potential

with much greater ease than can the soma.

If the wave is strong enough, and reaches the axon

hillock then this graded potential will lead to the

generation of the action potential.

If it does not reach the axon hillock, then the graded

potential will automatically die off and NO action

potential will be generated.

Question: The action potential does not occur adjacent

to the excitatory synapses. WHY?

What are the differences between Action and Graded Potential?

DIFFERENCES B/W GRADED & ACTION POTENTIAL

PROPERTY GRADED POTENTIAL ACTION POTENTIAL

Triggering eventStimulus by combination of NT

with receptor leading to change in permeability

Triggered by Dep. to threshold, usually by a graded potential or AP

Ion movement producingchange in Potential

Na+, K+, Cl- or Ca2+ by various means

Sequential movement of Na+

into & K+ out of the cell by voltage gated channels

Duration Varies with stimulus duration Constant

Direction of Pot. Change Can be Dep. Or Hyperpol. Always Depolarization

Location Usually dendrites & cell body Usually axon hillock & Trigger zone

Decremental in magnitude with distance

YES No

Summation YES NO

All or None Law NO YES

Refractory Period NO YES

The reason for this is that the amount of transmitter substancereleased by a single synapse causes an EPSP no greater than 0.5to 1 millivolt, instead of the 10 to 20 millivolts normally requiredto reach threshold for excitation.

Why doesn’t the discharge of a single synapse on the surface of a neuron almost never excites the

neuron?

PROPERTIES OF

SYNAPSES

1. DALE’S LAW

This law states:

At a given chemical synapse only one type of

neurotransmitter is released and thus only one effect,

either excitatory or inhibitory, is possible.

2. SYNAPTIC DELAY

Definition:

It is the time taken for the neurotransmitter to be released

from the presynaptic membrane, diffuse across the

synaptic cleft to reach the post synaptic membrane and

bind to the neuroreceptors there.

It is about 0.5 msec.

3. ONE-WAY TRAVEL

In a chemical synapse the impulse always travels in one

direction only, from the presynaptic to the postsynaptic

cell. This is because the neurotransmitter is only

released from the presynaptic terminal.

What happens when multiple synapses summate?

4. SUMMATION IN SYNAPSES

A Word of Warning!

Discharge of a single presynaptic terminal can never

increase the neuronal potential from −65 millivolts all the

way up to −45 millivolts.

About 40 to 80 synapses must discharge for a single

anterior motor neuron (at the same time or in rapid

succession) for the threshold to be reached. This process

is called summation.

For each excitatory synapse that discharges simultaneously,

the total intrasomal potential becomes more positive by 0.5 to

1.0 mv.

When the EPSP becomes great enough, the threshold for

firing will be reached and an action potential will develop

spontaneously in the initial segment of the axon.

SPATIAL

SUMMATION

The effect of summating

simultaneous postsynaptic

potentials by activating

multiple terminals on

widely spaced areas of the

neuronal membrane

simultaneously is called

spatial summation.

By the process of

summation, the result is

greater than the strength

of a single synapse.

TEMPORAL

SUMMATION

Successive discharges

from a single presynaptic

terminal, if they occur rapidly

enough, can add to one

another; that is, they can

“summate.” This type of

summation is called temporal

summation.

By the process of summation,

the result is greater than the

strength of a single synapse.

What happens if an IPSP is trying to excite the neuron

while an EPSP is trying to inhibit it at the same time?

The two effects can partially or completely nullify each other.

Thus, if a neuron is being excited by an EPSP, an inhibitory

signal from another source can often reduce the postsynaptic

potential to less than threshold value for excitation, thus turning

off the activity of the neuron.

5. CONVERGENCE &

DIVERGENCE

Usually the postsynaptic

neuron receives afferents

from a large number of

neurons.

This means that a number

of neurons will synapse on

a single neuron. This is

called Convergence.

1:1 convergence is rare.

Same rules apply for

Divergence.

6. FACILITATION OF NEURONS

Often the summated postsynaptic potential is excitatory but has not

risen high enough to reach the threshold for firing by the postsynaptic

neuron.

When this happens, the neuron is said to be facilitated.

Its membrane potential is nearer to the threshold for firing than normal,

but not yet at the firing level.

Consequently, another excitatory signal entering the neuron from some

other source can then excite the neuron easily.

7. EFFECTS OF CHEMICAL CHANGES

IN THE BLOOD

• Acidosis depresses while alkalosis increases the

neuronal activity. (Thus, acidosis predisposes a person

to coma while alkalosis predisposes a person to epileptic

seizures.)

• Hypoxia exerts a depressing effect. (When cerebral

blood flow is interrupted even for a few seconds, the

person becomes unconscious.)

8. FATIGUE

Fatigue can occur due to the following reasons:

1. If there is continuous stimulation of the presynaptic synapse, this

leads to exhaustion or partial exhaustion of the neurotransmitter

stores. If all NT stores are depleted, the synaptic transmission may

stop.

2. Progressive inactivation of postsynaptic membrane receptors.

3. Slow development of abnormal conc. of ions inside the

postsynaptic neuron.

Question: What can be the advantage of fatigue?

When areas of the nervous system become overexcited, fatigue causes

them to lose the excess excitability after a while. E.g. during

epileptic seizure.

9. Effect of Drugs

• Caffeine, Theophylline and Theobromine all increase neuronal

excitability (by reducing the threshold for neuronal excitation).

• Strychnine increases neuronal excitability (by inhibiting the action

of Inhibitory NT leading to severe tonic muscle spasms.)

• Most anaesthetics decrease neuron excitability by increasing the

threshold for excitation.

NEUROTRANSMITTERS VS

NEUROMODULATORS

NEUROTRANSMITTERS vs NEUROMODULATORS

Characteristic NEUROTRANSMITTERS NEUROMODULATORS

Size Small Molecule

Initially large molecule later

split into smaller fragments

Site of synthesis Cytosol of Presynaptic

terminal

Cytosol of Cell body

Duration of action Short (within milliseconds) Long (minutes to days to

months)

Potency Less Potent More Potent

Quantity required for

effective action More Less

Example of action transmission of sensory

signals to the brain and of

motor signals back to the

muscles.

long term changes in no. of

neuronal receptors, long-

term opening & closure of

ion channels, & long-term

changes in number of

synapses or sizes of

synapses

Example Ach, NE, E, Dopamine,

Serotonin

TRH, GH, Substance P

Thus, neurotransmitters are involved in rapid

communication, whereas neuromodulators tend to be

associated with slower events such as learning,

development, motivational states, or even some

sensory or motor activities.