    

Neurons

A nerve cell capable of generating and transmitting electrical signals Vary in structure and properties Use the same basic mechanisms to send signals Generate action potentials or passive potential Communicate with other neurons or cells via synaptic connections (electrical or chemical)

Neurons

Structural Diversity of Neurons

Figure 5.18a

Neuron Classification Based on Structure Figure 5.18c

Neuron Classification Based on Function

Figure 5.18b

Neural Zones

Four functional zones



Signal reception

: dendrites and the cell body (soma)   - Incoming signal is received and converted to a change in

membrane potential

Signal integration

: axon hillock - Strong signal 

action potential (AP)

Signal conduction

: axon; some wrapped in myelin sheath - AP travels down axon 

Signal transmission

: axon terminals

- Neurotransmitter

is released

Neural Zones, Cont.

Figure 5.2

Electrical Signals in Neurons

 Neurons have a resting membrane potential (like all cells)  Neurons are

excitable

; can rapidly change their membrane potential  Changes in membrane potential act as electrical signals

Figure 5.3

Measuring the voltage

 Use microelectrodes to measure the voltage between outside and inside  Conducting fluid such as KCL is used  Reference electrode is placed in the bathing medium  Potentiometer will measure the potential ie resting potential

Membrane Potential

Three factors contribute to the membrane potential  The distribution of ions membrane across the plasma  The relative permeability to these ions  The charges of the ions of the membrane

►Nernst equation

can be used to measure the potential of a cell ie the voltage difference between the inside and the outside of the cell.

Membrane Potential

EK + = (1.9872*295)/(1*23062) ln (4/139) = - 88 mV at 22 o C ENa + = (1.9872*295)/(1*23062) ln (145/12) = 62 mV at 22 o C ECl = (1.9872*295)/(-1*23062) ln (116/4) = - 84 mV at 22 o C

Resting potential

Origin of the resting potential in a typical vertebrate neuron.

 

A - negatively charged proteins Resting neuron: 10 times more open K + channels than Na + or Cl channels



Outside of cell is more positive relative to the inside of the cell

 

So the resting potential is closest to the Nernst potential for K +



K + is dominant because its permeability is greatest (P K ). This is due to leak channels Also have leakage of Na (P Cl ) + (P Na ) and Cl -

Resting potential

Actual measurements of membrane potential

  

Measured in giant axon of squid Found resting potential of -65 to -70 mV

  

So other ions are influencing the resting potential!!



Increased external K + to determine new membrane potential Found a slope of – 58 mV ► means that for every ten fold increase in external K + the potential will increase by 58 mV at room temperature Permeability of Na + and Cl the presence of proteins. ions and Use Goldman equation to calculate the resting potential

Resting potential

Membrane Potential



Nernst equation predicts membrane potential for a single ion



Goldman equation for the membrane potential (E

m

): predicts the membrane potential using multiple ions

Em



RT F

ln

P K

[

K P K

[

K

  ]

o

]

i



P

 [

Na



NA P NA

[

Na

 ] ]

i o

 

P Cl

[

Cl P Cl

[

Cl

  ] ]

o i Chloride ion has a charge opposite to the two cations, a correction is needed to prevent the cations and anion from canceling each other. Thus, the statement of relative chloride ion concentrations is inverted — inside over outside

In the giant squid: P K + : P Na + : P Cl = 1 : 0.04 : 0.45

Membrane Potential

Effects of changing the ion permeability The resting membrane potential is -53 mV; ENa, EK, and ECl are the potentials calculated from the Nernst equation if the membrane contains only open channels for Na + or K + or Cl , respectively.

Membrane Potential

Lets do some calculations



Electrical signals

• • •

Changes in Channel permeability create Electrical signals!

Mechanically gated ion channels

•

Sensory neurons. Open in response to pressure or stretch Chemically gated ion channels

•

Respond to ligands Voltage gated Na

• •

+ channels Respond o changes in membrane potential Voltage gated K + channels or CA 2+ channels

Graded Potential vs. Action Potential

Two types of electrical signals

Action potentials

Active conduction



Passive conduction of signal is limited by properties of the nerve and signal is reduced over distance



Active conduction ie action potentials (AP) - Signal travels along nerve with no loss of amplitude

Action Potentials (AP)

• • • Occurs only when the membrane potential at the axon hillock reaches threshold • Three phases • Depolarization • Repolarization • Hyperpolarization

Absolute refractory period

– incapable of generating a new AP

Relative refractory period

– more difficult to generate a new AP

Figure 5.10

Voltage-Gated Channels

• Change shape due to changes in membrane potential • Positive feedback, e.g., influx of Na + depolarization    number of open Na +  local channels • Na + channels open first (depolarization) • K + channels open more sloooooowly (repolarization) • Na + channels close • K + channels close slooooowly (relative refractory period)

Channels of an Action potentials

Voltage gated Na + channels: 3 states: closed, open, inactive Closed to open:

-

Depolarization is necessary to open the channel Acts to activate itself in a regenerative cycle

-

More Na+ influx depolarizes the membrane which opens more channels which depolarizes the membrane more.

Open to Inactive:

-

Depolarization is also necessary to inactive the channel Once the channel is open it will then also switch to the inactive state and can not be opened again

-

Inactive to closed: The channel will not switch back to the closed state until the membrane has repolarized (i.e. gone back towards the original resting membrane potential Once in the closed state it can then be reopened

Na

+

Channels Have Two Gates

• Activation gate – voltage dependent • Inactivation gate – time-dependent

Na

+

Channels Have Two Gates

Channels of an Action potentials

Voltage gated K + channels (delayed rectifying K + channel): 2 states: closed and open

-

Closed to open: Strong depolarization is necessary to open the channel Hyperpolarizes the cell

-

Brings membrane back towards Nernst potential for K +

-

Open to Closed: Will close when the membrane becomes hyperpolarized Works to shut itself down

Voltage-Gated Channels, step by step

Figure 5.12

Action Potentials Travel Loooong Distances

• • • •

“All-or-none”

– occurs or does not occur; identical without degradation

Self propagating

- an AP triggers the next AP in adjacent areas of the axonal membrane

Electronic current spread

in between ion channels

Cycle:

Ion entry  spread  electronic current triggering AP

Components of an Action potentials

Components of an Action potentials

Threshold



Most neurons have a threshold at -50 mV (i.e. 10 to 15 mV depolarization)



Action potential is an all or none event. If a nerve is at rest the amplitude



on one action potential will be the same all along the nerve independent of the stimulus strength Threshold reflects the need to trigger the opening of the voltage-gated sodium channel (need a depolarization of about 10 to 15 mV to open) Rising phase



Sodium channels open



Na + ions flow into cell

 

Depolarizes the cell More and more sodium channels open = a regenerative response regenerative opening of sodium channels drives the membrane potential towards a peak of the Nernst equilibrium potential for Na +

Components of an Action potentials

Peak



During an action potential the membrane potential goes towards the



Nernst equilibrium potential for Na + In terms of Goldman-Katz equation now permeability to Na + (K

+

and Cl is dominant minor components) therefore membrane potential goes towards



E Na Usually falls short of E Na , less driving force on Na+ and the channels begin to inactivate rapidly after activation

Components of an Action potentials

Fall



Membrane potential falls back towards rest - Why doesn't the action potential stay around ENa?

Two reasons: i) Na+ channels move into an inactive state ii) delayed K+ channels open



Inactivating Na+ channels - Na+ channels go to an inactivated state after 1-2 msec after first opening - inactivated = can NOT be reopened - Membrane potential now determined mostly by K+ (same as for resting potential) and membrane starts to repolarize



Delayed K+ channels open (delayed rectifier; voltage-gated like Na+ channel) - open after about 1-2 msec of threshold depolarization - now K+ flows out of the cell and speeds the repolarization process - cause the hyperpolarization after the action potential - open K+ channels make the K+ permeability higher than at rest - membrane more negative on inside hyperpolarization of membrane causes K+ channels to close - Membrane settles back to rest

Components of an Action potentials

Repolarization

 

Voltage-gated Na+ channels and voltage-gated K+ channels now closed Membrane goes back to the resting state - i.e. the leak channels are the only channels open and again set the membrane potential

Refractory period (RP)

Absolute RP



Na + channels are inactive and CAN NOT be opened no matter how much the membrane is depolarized at this time



another action potential can not be generated Relative RP



as membrane repolarizes ----



goes to more negative potentials this triggers the Na + channels to move

  

from an inactive state to a close state hyperpolarization by the opening of the K + channels helps this process once Na + channel is in the closed state it can be opened again with depolarization during relative RP, more and more Na + channels available to be opened and therefore increase the chances of firing an action potential

Refractory period (RP)

Frequency of AP

How does a nerve communicate the strength of a stimulus?

     

Information is given by the frequency of the AP along the nerve Stimulus strength triggers different frequency of AP For example: light touch – infrequent AP; rough touch – more frequent AP Refractory period limits the frequency of AP During the relative RP an AP can be generated but has to be at supra threshold overcome the hyperpolarization because it has to Will be at decreased amplitude because fewer Na + channels are available to open

Direction of AP

Unidirectional conduction of an action potential due to transient inactivation of voltage-gated Na+ channels

Action Potentials Travel Loooong Distances

• Triggered by the net graded potential at the

axon hillock

(trigger zone) • Do not degrade • Travel looong distances • All-or-none • Must reach

threshold potential

to fire

Figure 5.7

Action Potentials Travel Looong Distances Figure 5.13 (1 of 2)

Action Potentials Travel Looong Distances Figure 5.13 (2 of 2)

• •

Signals in the Dendrites and Cell Body

Incoming signal, e.g., neurotransmitter Membrane-bound receptors

transduce

the chemical signal to an electrical signal by changing the membrane potential (

graded potential

)

Graded Potentials

• Vary in magnitude depending on the strength of the stimulus • e.g., more neurotransmitter  more ion channels will open

Graded Potentials

• Ions move down an electrochemical gradient • Net movement stops when the

equilibrium potential

is reached • Can depolarize (Na + Ca 2+ channels) or hyperpolarize (K + and and Cl channels) the cell

Graded Potentials Travel Short Distances

•

Conduction with decrement

–  strength with  distance from opened ion channel • Due to • Leakage of charged ions across the membrane • Electrical resistance of the cytoplasm • Electrical properties of the membrane •

Electrotonic current spread

– positive charge spreads through the cytoplasm causing depolarization of the membrane • Can be

excitatory

or

inhibitory

Graded Potentials Travel Short Distances

Integration of Graded Signals

• • • Many graded potentials can be generated simultaneously • Many receptor sites • Many kinds of receptors

Temporal summation

– graded potentials that occur at slightly different times can influence the net change

Spatial summation

– graded potentials from different sites can influence the net change

Figure 5.9

Spatial summation

Temporal summation

Integration of Graded Signals, Cont.

Figure 5.8

Back to Neuron structure

Myelination

• • • Vertebrate neurons are myelinated

Myelin

– insulating layer of lipid-rich around the axon

Schwann cells

wrapped

Glial cells

– supportive neural cells, e.g., Schwann cells

Myelination, Cont.

Figure 5.14

Myelination, Cont.

• • •

Nodes of Ranvier

– areas of exposed axonal membrane in between Schwann cells

Internodes

– the myelinated region

Saltatory conduction

– APs “leap” from node to node; APs at nodes of Ranvier and electrotonic current spread through internodes

Myelinated Neurons in Vertebrates

Disadvantage of large axons • Take up a lot of space which limits the number of neurons that can be packed into the nervous system • Have large volumes of cytoplasm making them expensive to produce and maintain Myelin enables rapid signal conduction in a compact space

Myelin Increases Conduction Speed

• •    membrane resistance: act as insulators  current loss through leak channels membrane resistance   l   capacitance: layer    thickness of insulating capacitance constant of membrane     time to conduction speed • Nodes of Ranvier are needed to boost depolarization

Glial Cells

• Most neural cells (90% in human brain) • Cannot generate APs • Five main types • • • • •

Schwann cell

– form myelin in motor and sensory neurons of the PNS

Oligodendrocyte

– form myelin in the CNS

Astrocyte

– transport nutrients, remove debris in CNS

Microglia

– Remove debris and dead cells from CNS

Ependymal cells

– line the fluid-filled cavities of the CNS

Figure 5.19

Unidirectional Signals

• Stimulus starts at the axon hillock and travels towards the axon terminal • Up-stream Na + channels (just recently produced an AP) are in the

absolute refractory period

• • The absolute refractory period prevents backward transmission and summation of APs

Relatively refractory period

also contributes by requiring a very strong stimulus to cause an AP

The Synapse

• • • • • Signal transmission zone

Synapse

– synaptic cleft, presynaptic cell, and postsynaptic cell

Synaptic cleft presynaptic

– space in between the and

postsynaptic

cell

Postsynaptic cell

– neurons, muscles, and endocrine glands

Neuromuscular junction

– synapse between a motor neuron and a muscle

Diversity of Synaptic Transmission

Figure 5.26

Electrical and Chemical Synapses

Electrical synapse Chemical synapse

Rare in complex animals Common in simple animals Fast Common in complex animals Rare in simple animals Slow Bi-directional Postsynaptic signal is similar to presynaptic Excitatory Unidirectional Postsynaptic signal can be different Excitatory or inhibitory

Chemical Synapse Diversity

Vary in structure and location

Figure 5.27

Neurotransmitters

Characteristics • • Synthesized in neurons Released at the presynaptic cell following depolarization • Bind to a postsynaptic receptor and causes an effect

Neurotransmitters, Cont.

More than 50 known substances Categories • • • • • Amino acids Neuropeptides Biogenic amines Acetylcholine Miscellaneous Neurons can synthesize many kinds of neurotransmitters

Neurotransmitter Action

Inhibitory neurotransmitters • • Cause hyperpolarization Make postsynaptic cell less likely to generate an AP Excitatory neurotransmitters • • Cause depolarization Make postsynaptic cell more likely to generate an AP

Neurotransmitter Receptor Function

Ionotropic • • • Ligand-gated ion channels Fast e.g., nicotinic ACh Metabotropic • • Channel changes shape Signal transmitted via secondary messenger • Ultimately sends signal to an ion channel • • Slow Long-term changes

Figure 5.28

Ca 2+ Regulates Neurotransmitter Release Figure 5.16

• • •

Amount of Neurotransmitter

Influenced by AP frequency which influences Ca 2+ concentration • • • Control of [Ca 2+ ] Open voltage-gated Ca 2+ channels  Binding with intracellular buffers  [Ca [Ca 2+ ] 2+ ] Ca 2+ ATPases  [Ca 2+ ] High AP frequency  high [Ca 2+ ]  influx is greater than removal many synaptic vesicles release their  contents  high [neurotransmitter]

Acetylcholine

Primary neurotransmitter at the vertebrate neuromuscular junction

Figure 5.17

Synaptic Plasticity

• • • • Change in synaptic function in response to patterns of use

Synaptic facilitation

–  APs   neurotransmitter release

Synaptic depression

release –  APs   neurotransmitter

Post-tetanic potentiation

frequency APs   (PTP) – after a train of high neurotransmitter release

Figure 5.32

Long-term potentiation

Postsynaptic Cells

Have specific receptors for specific neurotransmitters e.g., Nicotinic ACh receptors

Signal Strength

• Influenced by neurotransmitter amount and receptor activity • Neurotransmitter amount: Rate of release vs. rate of removal • Release: due to frequency of APs • Removal • Passive diffusion out of synapse • Degradation by synaptic enzymes • Uptake by surrounding cells • Receptor activity: density of receptors on postsynaptic cell

Diversity of Signal Conduction

So far: • • • • Electrotonic Action potentials Saltatory conduction Chemical and electrical synapses Also: • • Shape and speed of action potential Due to diversity of Na + and K + channels

• • • • •

Ion Channel Isoforms

Multiple isoforms Encoded by many genes Variants of the same protein Voltage-gated K + channels are highly diverse (18 genes encode for 50 isoforms in mammals) Na + channels are less diverse (11 isoforms in mammals)

Table 5.2

Channel Density

Higher density of voltage-gated Na + channels  Lower

threshold

 Shorter

relative refractory period

Voltage-Gated Ca

2+

Channels

• Open at the same time or instead of voltage-gated Na + channels • Ca 2+ enters the cell causing a depolarization • Ca 2+ influx is slower and more sustained • Slower rate of APs due to a longer refractory period • Critical to the functioning of cardiac muscle

Conduction Speed

Two ways to increase speed: myelin and increasing the diameter of the axon

Table 5.3

Cable Properties

• • Similar physical principals govern current flow through axons and telephone cables

Current

(

I

) – amount of charge moving past a point at a given time • A function of the drop in

voltage

(

V

) across the circuit and the

resistance

(

R

) of the circuit • •

Voltage

– energy carried by a unit charge

Resistance

– force opposing the flow of electrical current • Ohm’s law:

V

=

IR

Cable Properties, Cont.

• Ions moving through voltage-gated channels cause a current across the membrane • Current spreads electrotonically • Some current leaks out of the axon, and flows backwards along the outside of the axon, completing the circuit

Figure 5.20ab

Cable Properties, Cont.

Each area of axon consists of an electrical circuit • • Three resisters: extracellular fluid (

R e

), the membrane (

R m

), and the cytoplasm (

R c

) A capacitor (

C m

) – stores electrical charge; two conducting materials (ICF and ECF) and an insulating layer (phospholipids)

Figure 5.20c

Voltage Decreases With Distance

•

Conduction with decrement

• Due to resistance • Intracellular fluid: high resistance  • Extracellular fluid: high resistance    decrement decrement • Membrane: high resistance   decrement • K + out leak channels (always open): some + charge leaks   current • Few K + leak channels   + charge leak out  high membrane resistance

• • •

Length Constant (

l

)

Distance over which change in membrane potential will decrease by 37% (1/

e

)

r o

is usually low and constant l is largest when

r m

high and

r i

is low is l 

r m

/(

r i



r o

) l 

r m

/

r i

Figure 5.21

Speed of Conduction and Resistance

• Axonal conduction is a combination of electrotonic current flow and APs • Electrotonic current flow is much faster than APs • But, electronic current flow is graded and can travel only short distances • Greater l /APs   more electrotonic current flow faster speed of conduction

Speed of Conduction and Capacitance

•

Capacitance

– quantity of charge needed to create a potential difference between two surfaces of a capacitor • Depends on three features of the capacitor • Material properties: generally the same in cells • Area of the two conducting surfaces:  area   capacitance • Thickness of the insulating layer:  capacitance thickness  

Speed of Conduction and Capacitance

• Time constant ( t ) - time needed to charge the capacitor; t • Low

r m

or faster 

c m

=

r m c m

 low t  capacitor becomes full faster depolarization  faster conduction

Giant Axons

• Easily visible to the naked eye • Not present in mammals

Figure 5.24

Giant Axons Have High Conduction Speed

•

r m

is inversely proportion to surface area:  diameter     surface area resistance   leak channels •

r i

 is inversely proportional to volume:   volume   resistance • Effect of resistance l  • 

r m

  l   conduction speed • 

r i

  l   conduction speed diameter

r m

/

r i

• Do not cancel each other out:

r m

to radius,

r i

is proportional is proportional to radius 2 • Therefore, net effect of increasing radius of the axon is to increase the speed of conduction

Giant Axons Have High Conduction Speed

Figure 5.25