Synapses and SynapticSynapses and SynapticTransmissionTransmission

Dr Fawzia ALRoug, MBBS, Master, Ph.D Dr Fawzia ALRoug, MBBS, Master, Ph.D Assistant Professor, Department of Physiology, Assistant Professor, Department of Physiology, College of Medicine, King Khalid University Hospital, College of Medicine, King Khalid University Hospital, Riyadh, Saudi ArabiaRiyadh, Saudi Arabia

INTRODUCTION TO SYNAPSE:INTRODUCTION TO SYNAPSE:

The CNS contains more than 100 billion neurons.

Incoming signals enter the neuron through synapses located mostly on the neuronal

dendrites, but also on the cell body. For different types of neurons, there may be

only a few hundred or as many as 200,000 such synaptic connections from input fibers.

Conversely, the output signal travels by way of a single axon leaving the neuron.

What is a synapse?What is a synapse?

A junction where the axon or some other portion of A junction where the axon or some other portion of one cell (= presynaptic cell) terminates on the one cell (= presynaptic cell) terminates on the dendrites, soma, or axon of another neuron (post dendrites, soma, or axon of another neuron (post synaptic cell). synaptic cell). The term was introduced in nineteenth century by the British neurophysiologist Charles Sherrington

What happens at the synapse?What happens at the synapse?

Information is transmitted in the CNS mainly in the Information is transmitted in the CNS mainly in the form of APs “=nerve impulse”, which pass from one form of APs “=nerve impulse”, which pass from one neuron to another.neuron to another.

Each impulse from its way from one neuron to Each impulse from its way from one neuron to another may:-another may:-

1.1. Be blocked in its transmission from one Be blocked in its transmission from one neuron to anotherneuron to another

2.2. Be changed from single impulse to repetititve Be changed from single impulse to repetititve impulses.impulses.

Synaptic transmission is a complex process that Synaptic transmission is a complex process that permits grading and adjustment of neural activity permits grading and adjustment of neural activity necessary for normal function.necessary for normal function.

Anatomical Types of Synapses

Figure 11.17

• Axodendritic – synapses between the axon of one neuron and the dendrite of another

• Axosomatic – synapses between the axon of one neuron and the soma of another

• Other types of synapses include:– Axoaxonic (axon to axon)– Dendrodendritic (dendrite to dendrite)– Dendrosomatic (dendrites to soma)

Anatomical Types of Synapses

Types of synapses ( functional classificationTypes of synapses ( functional classificationor Types of comnication)or Types of comnication)

A.Chemical synapseA.Chemical synapse

Almost all synapses used for signal Almost all synapses used for signal transmission in the CNS of human transmission in the CNS of human being are chemical synapses.being are chemical synapses. i.e. first neuron secretes a chemical i.e. first neuron secretes a chemical substance called neurotransmitter at substance called neurotransmitter at the synapse to act on receptor on the the synapse to act on receptor on the next neuron to excite it, inhibit or next neuron to excite it, inhibit or modify its sensitivity.modify its sensitivity.

– Are less common than chemical synapses– Correspond to gap junctions found in other

cell types– Are important in the CNS in:

Arousal from sleep• Mental attention• Emotions and memory• Ion and water homeostasis

B. Electrical SynapsesMembranes of the pre- and post-Membranes of the pre- and post-synaptic neurons come close synaptic neurons come close together and gap junctions forms together and gap junctions forms low membrane borders which low membrane borders which allow passage of ionsallow passage of ions. .

Conjoint synapseConjoint synapseBoth electrical and chemical.Both electrical and chemical.Examples for 2,3 Examples for 2,3 neurons in neurons in lateral vestibular nucleus.lateral vestibular nucleus.

Examples of synapses outside CNSExamples of synapses outside CNS

1.1.NMJNMJ

2.2.Contact between Contact between autonomic autonomic neurons and neurons and smooth and smooth and cardiac musclescardiac muscles

Functional Anatomy of a SynapseFunctional Anatomy of a Synapse

SYNAPSE: STRUCTURE & FUNCTIONS SYNAPSE: STRUCTURE & FUNCTIONS

Synaptic cleft: This the space between the axon terminal and sarcolemma. It has a width of

200-300 angstroms

Synaptic knobs (presynaptic terminal ) cover Synaptic knobs (presynaptic terminal ) cover

about 40% of somaabout 40% of soma

and 70% of dendritic membraneand 70% of dendritic membrane

CHEMICAL ACTIVITY AT SYNAPSE: CHEMICAL ACTIVITY AT SYNAPSE:

Action of the transmitter substance onAction of the transmitter substance onpost-synaptic neuron:post-synaptic neuron:

At the synapse, the membrane of post-At the synapse, the membrane of post-synaptic neuron contains large number of synaptic neuron contains large number of receptor proteins.receptor proteins.

These receptors have two componentsThese receptors have two components

1. Binding site that face the cleft to bind the neurotransmitter

2. Ionophore: It passes all the way through the membrane to the interior. It is of two types

Ion channels 2nd messenger system in the post-synaptic membrane.This mechanism is important where prolonged post-synaptic changes are needed to stay for days, months . . Years (memory).Channels are not suitable for causing prolonged post-synaptic changes as they close in milliseconds.

Cation channelsNa+ (most common)K+Ca++Opening of Na+ channels membrane potential in positive direction toward threshold level of excitation (+) neuron

Anion channelsCl¯ (mainly)Opening of Cl¯ channels diffusion of negative charges into the membrane membrane potential making it more negative away from threshold level (-) neuron

1.1. Opening of ion channel [open for prolonged Opening of ion channel [open for prolonged time]time]

2.2. Activation of cAMP Activation of cAMP long-term changes long-term changes [memory][memory]

3.3. Activation of intracellular enzymes Activation of intracellular enzymes cellular cellular chemical activatorschemical activators

4.4. Activate gene transcription Activate gene transcription protein + protein + structural changes [memory] long-term memorystructural changes [memory] long-term memory

Most common type of 2Most common type of 2ndnd messenger in messenger in neurons is G-proteinneurons is G-protein

The second messenger system

Fate of neurotransmitterFate of neurotransmitter

After a transmitter substance is released at a synapse, it After a transmitter substance is released at a synapse, it must be removed by:-must be removed by:-

Diffusion out of synaptic cleft into Diffusion out of synaptic cleft into surrounding fluidsurrounding fluid

Enzymatic destruction e.g. Ach esterase Enzymatic destruction e.g. Ach esterase for Achfor Ach

Active transport back into pre-synaptic Active transport back into pre-synaptic terminal itself e.g. norepinephrineterminal itself e.g. norepinephrine

Neurotransmitter bound to a postsynaptic neuron: Produces a continuous postsynaptic effectBlocks reception of additional “messages”

Electrical events in post-synaptic neurons:Electrical events in post-synaptic neurons:

1. RMP of neuronal soma:1. RMP of neuronal soma:~~ 65mV i.e. less than sk. ms. [65mV i.e. less than sk. ms. [70 to 70 to 90mV]90mV]

- If the voltage is less negative If the voltage is less negative the neuron is the neuron is excitableexcitable

Causes of RMP:Causes of RMP:1.1. Leakage of K+ (high K+ permeability)Leakage of K+ (high K+ permeability)2.2. Large number of negative ions inside: proteins, Large number of negative ions inside: proteins,

phosphatephosphate3.3. Excess pumping of Na+ out by Na+-K+ pump Excess pumping of Na+ out by Na+-K+ pump

22. Effect of synaptic excitation on post-. Effect of synaptic excitation on post-synaptic membrane:synaptic membrane: = Excitatory post-synaptic potential = Excitatory post-synaptic potential [EPSPs][EPSPs]When excitatory neurotransmitter bind to When excitatory neurotransmitter bind to its receptor on post-synaptic membrane its receptor on post-synaptic membrane partial depolarization [partial depolarization [ Na influx] of post- Na influx] of post-synaptic cell membrane immediately synaptic cell membrane immediately under presynaptic ending, i.e. EPSPsunder presynaptic ending, i.e. EPSPsIf this potential rises enough to threshold If this potential rises enough to threshold level level AP will develop and excite the AP will develop and excite the neuron (central or neuronal summation)neuron (central or neuronal summation)

This summation will cause the membrane This summation will cause the membrane potential to increase from potential to increase from 65mV to 65mV to 45mV.45mV.

EPSPs = +20mV which reaches the EPSPs = +20mV which reaches the membrane to the firing level membrane to the firing level AP develops at AP develops at axon hillock.axon hillock.

N.B. Discharge of single pre-synaptic terminal N.B. Discharge of single pre-synaptic terminal can never increase the neuronal potential from can never increase the neuronal potential from 65mV to 65mV to 45mV.45mV.

EPSP is produced by the action of an excitatory EPSP is produced by the action of an excitatory neurotransmitter neurotransmitter depolarization of post- depolarization of post-synaptic membrane.synaptic membrane.

The excitatory neurotransmitter opens Na+ or The excitatory neurotransmitter opens Na+ or Ca++ channels Ca++ channels depolarization of the area depolarization of the area under the pre-synaptic membrane.under the pre-synaptic membrane.

EPSPs:EPSPs:• Graded responseGraded response• Proportionate to the strength of the stimulusProportionate to the strength of the stimulus• Can be summatedCan be summated• If large enough to reach firing level If large enough to reach firing level AP is AP is

producedproduced

Post-synaptic potential of +10 to +20mV is Post-synaptic potential of +10 to +20mV is needed to produce APneeded to produce AP

Excitatoy Postsynaptic PotentialExcitatoy Postsynaptic Potential

Inhibitory post-synaptic Inhibitory post-synaptic potentialspotentialsStim. of some inputs [=pre-synaptic terminals] Stim. of some inputs [=pre-synaptic terminals] hyperpolarization of the post-synaptic memb. hyperpolarization of the post-synaptic memb. which is the IPSP.which is the IPSP.

Causes: it is produced by localized increase in Causes: it is produced by localized increase in membrane permeability to Clmembrane permeability to Cl¯ of post-synaptic ¯ of post-synaptic memb.memb. (produced by inhibitory neurotransmitter) (produced by inhibitory neurotransmitter) excitability and memb. potential becomes excitability and memb. potential becomes away from firing level.away from firing level.Also IPSP can be produced byAlso IPSP can be produced by:-:--Opening of K+ channels Opening of K+ channels outward movement outward movement of K+of K+-Closure of Na+ or Ca++ channelsClosure of Na+ or Ca++ channels-IPSP = -IPSP = 5mV5mV

Synaptic propertiesSynaptic properties

1. One-way conduction1. One-way conduction

Synapses generally permit conduction Synapses generally permit conduction of impulses in one-way i.e. from pre-of impulses in one-way i.e. from pre-synaptic to post-synaptic neuron.synaptic to post-synaptic neuron.

2. Synaptic delay2. Synaptic delay

Is the minimum time required for Is the minimum time required for transmission across the synapse.transmission across the synapse.This time is taken byThis time is taken by

Discharge of transmitter substance by pre-Discharge of transmitter substance by pre-synaptic terminalsynaptic terminalDiffusion of transmitter to post-synaptic Diffusion of transmitter to post-synaptic membranemembraneAction of transmitter on its receptorAction of transmitter on its receptorAction of transmitter to Action of transmitter to membrane membrane permeabilitypermeabilityIncreased diffusion of Na+ to Increased diffusion of Na+ to post-synaptic post-synaptic potentialpotential

Properties of synapsesProperties of synapses (con…) (con…)

3. Synaptic inhibition3. Synaptic inhibitionTypes:Types:

A. Direct inhibitionA. Direct inhibitionB. Indirect inhibitionB. Indirect inhibitionC. Reciprocal inhibitionC. Reciprocal inhibition

D. Inhibitory interneuronD. Inhibitory interneuron E. E. Feed forward inhibitionFeed forward inhibition F. Lateral inhibitionF. Lateral inhibition

A. Direct inhibitionA. Direct inhibition

Post-synaptic inhibition, e.g. some Post-synaptic inhibition, e.g. some interneurones in sp. cord that inhibit interneurones in sp. cord that inhibit antagonist muscles. Neurotransmitter antagonist muscles. Neurotransmitter secreted is Glycine.secreted is Glycine.

Occurs when an inhibitory neuron (releasing Occurs when an inhibitory neuron (releasing inhibitory substance) act on a post-synaptic inhibitory substance) act on a post-synaptic neuron leading to neuron leading to its hyperpolarization due its hyperpolarization due to opening of Clto opening of Cl¯ [IPSPs] and/or K+ channels.¯ [IPSPs] and/or K+ channels.

B. Indirect B. Indirect inhibitioninhibitionPre-synaptic inhibition. Pre-synaptic inhibition. This happens when an inhibitory synaptic This happens when an inhibitory synaptic knob lie directly on the termination of a pre-knob lie directly on the termination of a pre-synaptic excitatory fiber.synaptic excitatory fiber. The inhibitory synaptic knob release a The inhibitory synaptic knob release a transmitter which inhibits the release of transmitter which inhibits the release of excitatory transmitter from the pre-synaptic excitatory transmitter from the pre-synaptic fiber.fiber.The transmitter released at the inhibitory The transmitter released at the inhibitory knob is GABA. knob is GABA. The inhibition is produced by The inhibition is produced by Cl Cl¯ and ¯ and K+. e.g. occurs in dorsal horm K+. e.g. occurs in dorsal horm pain pain gating.gating.

C. Reciprocal inhibitionC. Reciprocal inhibition

Inhibition of antagonist activity is Inhibition of antagonist activity is initiated in the spindle in the agonist initiated in the spindle in the agonist muscle. muscle. Impulses pass directly to the motor Impulses pass directly to the motor neurons supplying the same muscle neurons supplying the same muscle and via branches to inhibitory and via branches to inhibitory interneurones that end on motor interneurones that end on motor neurones of antagonist muscle.neurones of antagonist muscle.

D. Inhibitory interneuronD. Inhibitory interneuron ( Renshaw cells)( Renshaw cells)

Negative feedback inhibitory interneuron of Negative feedback inhibitory interneuron of a spinal motor neuron .a spinal motor neuron .This feedback inhibition also occurs in:This feedback inhibition also occurs in:

Cerebral cortexCerebral cortex

Limbic systemLimbic system

Note that Renshaw cells Note that Renshaw cells are in spinal cordare in spinal cord

E. Feed forward inhibitionE. Feed forward inhibition occurs in the cerebellum to limit the duration occurs in the cerebellum to limit the duration of excitation.of excitation.

F. Lateral inhibitionF. Lateral inhibitionBecause of lateral inhibition, the lateral Because of lateral inhibition, the lateral pathways are inhibited more strongly. pathways are inhibited more strongly. This happens in pathways utilizing This happens in pathways utilizing most accurate localization. e.g. most accurate localization. e.g. movement of skin hairs can be well movement of skin hairs can be well located, temperature and pain are located, temperature and pain are poorly located.poorly located.

4. Summation4. Summation

a)a)Spatial summation. Spatial summation. When EPSP is in more than one When EPSP is in more than one

synaptic knob at same time.synaptic knob at same time.

a)a)Temporal summation. Temporal summation. If EPSP in pre-synaptic knob are If EPSP in pre-synaptic knob are

successively repeated without successively repeated without significant delay so the effect of the significant delay so the effect of the previous stimulus is summated to previous stimulus is summated to the nextthe next

Summation

Figure 11.21

5. Convergence and divergence5. Convergence and divergence

ConvergenceConvergenceWhen many pre-synaptic neurones When many pre-synaptic neurones converge on any single post-synaptic converge on any single post-synaptic neuron.neuron.

DivergenceDivergenceAxons of most pre-synaptic neurons Axons of most pre-synaptic neurons divide into many branches that divide into many branches that diverge to end on many post-synaptic diverge to end on many post-synaptic neuron.neuron.

6.Occlusion6.Occlusion

Expected response due to pre-Expected response due to pre-synaptic fibers sharing post-synaptic synaptic fibers sharing post-synaptic neurone [=overlap].neurone [=overlap].

Neuromodulation: non-synaptic Neuromodulation: non-synaptic action of a substance on neurons that action of a substance on neurons that alters their sensitivity to synaptic alters their sensitivity to synaptic stimulation or inhibition. e.g. stimulation or inhibition. e.g. neuropeptides, steroidsneuropeptides, steroids

7. Fatigue7. Fatigue

Exhaustion of nerve transmitter. Exhaustion of nerve transmitter. Fatigue: If the pre synaptic neurons are continuously stimulated there may be an exhaustion of the neurotransmitter. Resulting is stoppage of synaptic transmission.The post synaptic membrane become less sensitive to the neurotransmitter.

8. Long-term potentiation = LTP8. Long-term potentiation = LTP

Rapidly developing persistent Rapidly developing persistent enhancement of post-synaptic enhancement of post-synaptic potential response to pre-synaptic potential response to pre-synaptic stim. after brief period of rapidly stim. after brief period of rapidly repeated stimulation of pre-synaptic repeated stimulation of pre-synaptic neurone. neurone. Ca++ intracellular in post-synaptic Ca++ intracellular in post-synaptic membrane.membrane. Amygdala N-methyl-D-aspartate Amygdala N-methyl-D-aspartate NMDA receptors.NMDA receptors.

9. Long-term depression9. Long-term depressionFirst noted in HippocampusFirst noted in Hippocampus

Later shown Through brainLater shown Through brain

Opposite of LTPOpposite of LTP

synaptic strengthsynaptic strength

Caused by slower of pre-synaptic neuroneCaused by slower of pre-synaptic neurone

Smaller rise of Ca++Smaller rise of Ca++

Occure in amino 3 hydroxy -5-Occure in amino 3 hydroxy -5-

methylisoxazole4-propionate AMPA recepmethylisoxazole4-propionate AMPA recep

FACTORS EFFECTINF SYNAPATIC FACTORS EFFECTINF SYNAPATIC TRANSMISSION: ALKALOSISTRANSMISSION: ALKALOSIS

Normally, alkalosis greatly increases neuronal excitability.

For instance, a rise in arterial blood pH from the 7.4 norm to 7.8 to 8.0 often causes cerebral

epileptic seizures because of increased excitability of some or all of the cerebral neurons.

This can be demonstrated especially well by asking a person who is predisposed to epileptic

seizures to overbreathe. The overbreathing blows off carbon dioxide and

therefore elevates the pH of the blood momentarily

FACTORS EFFECTINF SYNAPATIC FACTORS EFFECTINF SYNAPATIC TRANSMISSION: TRANSMISSION: ACIDOSISACIDOSIS

Conversely, acidosis greatly depresses neuronal activity;

A fall in pH from 7.4 to below 7.0 usually causes a comatose state.

For instance, in very severe diabetic or uremic acidosis, coma virtually always

develops.

FACTORS EFFECTINF SYNAPATIC FACTORS EFFECTINF SYNAPATIC TRANSMISSION: TRANSMISSION: DRUGSDRUGS

Many drugs are known to increase the excitability of neurons, and others are known to decrease

excitability. For instance,

Caffeine, Theophyline,

Theobromine, which are found in coffee, tea, and cocoa, respectively,

All increase neuronal excitability, presumably by reducing the threshold for excitation of neurons.

FACTORS EFFECTINF SYNAPATIC FACTORS EFFECTINF SYNAPATIC TRANSMISSION: TRANSMISSION: DRUGSDRUGS

Strychnine is one of the best known of all agents that increase excitability of neurons.

However, it does not do this by reducing the threshold for excitation of the neurons; instead, it inhibits the

action of some normally inhibitory transmitter substances,

especially the inhibitory effect of glycine in the spinal cord.

Therefore, the effects of the excitatory transmitters become overwhelming,

and the neurons become so excited that they go into rapidly repetitive discharge, resulting in severe tonic

muscle spasms.