CBNS 106 ~ PRE MIDTERM LECTURE NOTES 6 TO 9

Action Potential Conduction Velocity

the main factor that affects conduction velocity is the rate of propagation of these depolarizing positive ions in front of the leading edge of the action potential

The opening of voltage-gated Na+ channels allows an influx of Na+ which produces depolarization, causing more voltage-gated Na+ channels to open

This is a positive feedback system and is the action in action potential

The further and faster the positive ions travel down the axon, the faster the action potential is propagated

two factors that influence the rate of ion travel down the axon:
--\> the internal resistance
--\> the membrane resistance

The internal resistance of the axon to flow of ions...

within the axon

the membrane resistance of the axon to ions...

crossing the membrane

Changing either Ri or Rm will change...

the conduction velocity

how is conduction velocity increased?

1. conduction velocity is increased by increasing the axon diameter, bc larger diameter axons have lower internal resistance (maximum conduction velocity in invertebrates is 20m/s \-- large axons)

2. also increased by increasing membrane resistance (maximum conduction velocity is ~100m/s \-- small axon diameter)

increasing conduction velocity via increasing membrane resistance

it's done with myelination (aka oligodendroglia)...strategy taken by vertebrates

Why does increasing Rm increase conduction velocity?

1. bc without myelin the increased concentration of positive ions ahead of the action potential leak out of the axon, reducing the concentration of positive ions inside the axon and thus decreasing the leading edge of depolarization

2. the action potential thus skips from node of Ranvier to node of Ranvier (this is known as saltatory conduction)

myelin reduces the loss of positive ions between the nodes of Ranvier, therefore...

a larger concentration of ions is kept inside the axon, causing more depolarization and thus opening more voltage-gated sodium channels and allowing more sodium to flow into the axon

Why not have the whole length of the axon ensheathed in myelin (ie. why are there nodes?)

1. because even with myelin the concentration of positive ions still decreases as the ions travel down the axon away from the origin of the action potential (the axon hillock), and at some point there wouldn't be enough of a depolarization to reach threshold

Ion pumps facts B.

ion pumps are enzymes embedded into the membrane

ion pumps c.

although a single action potential will have little effect on the concentration of Na+ and K+, with hundreds or thousands of action potentials the concentration gradients will diminish

this is corrected by the sodium/potassium pumps

ion pumps d.

one type of Na+/K+ ion pump...

3 Na+ ions out of the axon and 2 K+ ions in

Ion pumps e.

Higher concentrations of Na+ inside of the axon are sensed and...

cause an increase the rate of pumping

ion pumps f.

ATP is the power source or metabolic energy of the cell

1. approximately 70% of the metabolic energy consumed by the brain is used to drive ion pumps (approx. 20% of all energy in the body in used by the brain)

2. myelin decreased the amount of Na+ and K+ used for an action potential, so less energy is required to pump ions to reestablish the concentration gradient

A. under normal physiological conditions the action potential starts at the axons hillock and travels to the terminal

but action potentials can travel in both directions down the axon if they are experimentally initiated by simulating in the middle of the axon

B. what happens when two action potentials collide?

they annihilate each other b/c the refractory periods which follow the action potentials (one AP can't pass through the refractory membrane produced by another AP)

If it wasn't for the refractory periods,...

the entire membrane would depolarize every time there was an action potential (the refractory periods are essential for the action potential wave-form)

Postsynaptic Potentials (PSP)

initiate the action potential

\---\> their importance is that they are a decision making or computational mechanism "deciding" whether or not an action potential should be generated

Some characteristics of postsynaptic potentials

1. PSPs are graded in amplitude
2. PSPs are graded in duration
3. PSPs propagate decrementally, meaning they decrease in amplitude as they travel away from the locus of initiation
4. PSPs can vary in sign, meaning they can be either depolarizing or hyperpolarizing
5. PSPs have no refractory period
6. PSPs have no threshold for initiation

There are two types of postsynaptic potentials

1. Excitatory postsynaptic potential (EPSP)
2. Inhibitory postsynaptic potential (IPSP)

Some characteristics of the EPSP

1. The EPSP is always depolarizing
2. By definition an EPSP is any PSP that increases the probability that an action potential will be generated

Some characteristics of the IPSP

1. IPSPs are usually hyperpolarizing, but they can be depolarizing
2. By definitions an IPSP is a PSP that decrease the probability that an action potential will be generated

The primary mechanism for generating an EPSP is...

the opening of neurotransmitter-gated (aka, ligand-gated) ion channels for Na+/K+ (both ions flow through the same channel)

The mechanisms for generating an IPSP is...

the opening of transmitter-gated ion channels for K+ or for Cl- (different channels)

PSPs are initiated at the postsynaptic membrane and get smaller as they travel away from that point

the further away from the axon hillock that a postsynaptic potential is initiated, the less influence that PSP will have on generating an action potential

There are two forms of selectivity in these neurotransmitter-gated ion channels

1. these neurotransmitter-gated ion channels are selective for which neurotransmitter binds to their receptors (each receptor only binds one kind of neurotransmitter)

2. These neurotransmitter-gated ion channels are selective for the type of ions that can pass through their open channel

synaptic potentials are computational (or decision-making) mechanisms

they decide whether or not the neuron will generate an action potential

EPSPs and IPSPs can co-occur and...

the signals are integrated by the neuron

EPSPs and IPSPs are integrated in two different ways (2 different ways to summate),...

temporal summation, and spatial summation

Temporal summation

occurs when the same presynaptic axon fires multiple action potentials \-- results in summated PSPs

Spatial summation

occurs when multiple presynaptic axons fire action potential at the same time \-- results in summated PSPs

Postsynaptic potentials (PSPs) vs. action potentials

A. PSPs differ categorically from action potentials in every way

\---\> PSPs have no refractory period and action potentials do
\---\> PSPs are graded in amplitude and duration and action potential are stereotyped

Some reasons why PSPs and action potentials differ

1. PSPs have no refractory period because they are generated by the opening of neurotransmitter-gated channels in the membrane of the soma and dendrites and these ion channels have no inactivation gate

2. PSPs are graded in amplitude bc they are generated by the opening of neurotransmitter-gated ion channels and more neurotransmitter released from the presynaptic terminal opens more channels (there is no inactivation-gate to prevent this)

Mechanism for the production of EPSPs

A. EPSPs are generated by the opening of neurotransmitter-gated Na+/K+ ion channels

B. The maximum depolarization for the EPSP is to -9mv (b/c -9mv is the average of the equilibrium potentials of Na+ and K+ the two ions to which the membrane become permeable)

C. Opening Na+/K+ ion channels drive the membrane potential toward -9mv (the reverse potential) no matter what the starting voltage is

The reverse potential is the voltage at which...

the dominant flow of ions changes (aka reverses direction) \--- if the channel is permeable to only one ion, then the reversal potentials equals the equilibrium potential for that ion

the driving forces on sodium and potassium at -65mv results...

in a greater sodium influx than potassium efflux, thus causing depolarization

Mechanisms for the production of IPSPs

A. IPSPs are generated by the opening of either neurotransmitter-gated Cl- or neurotransmitter gated K+ channels

B. Opening of neurotransmitter-gated channels permeable to K+ will drive the membrane potential toward -80mv (the equilibrium potential of K+)

C. Below is a figure depicting the generation of an IPSP via the opening of neurotransmitter-gated Cl- channels

Why is the depolarization an IPSP?

Because the threshold for the generation of an action potential is -55mv, and the equilibrium potential of Cl- is -65mv \--- Cl- flux serves to clamp the membrane potential at -65mv which would decrease the probability of generation of an action potential

Definition of the IPSP

a decrease in the probability of generating an action potential

Information about gradients

A. The electrostatic force is a direct function of the membrane potential

B. Ions don't flow down their concentration gradients, they flow down their electrochemical gradients (two forces which can be in the same or opposite direction)

Mechanism of neurotransmitter release:

B. How is neurotransmitter released, or how is information transduced from electrical to chemical?

Ca++ \--- specifically the opening of the voltage-gated Ca++ channels in the terminal by an action potential allows for influx of Ca++ into the terminal, which causes neurotransmitter release

Neurotransmitter release 1

in the presynaptic terminal neurotransmitter vesicles are not randomly distributed \-- they are docked in the active zones

neurotransmitter release 2

in the active zone the vesicles fuse to the presynaptic membrane and release neurotransmitter

--\> some vesicles fuse with and become part of the presynaptic membrane as they release transmitter
--\> some vesicles "kiss" the presynaptic membrane and briefly open a small pore through which some of the transmitter escapes into the synaptic cleft. the pore then closes \-- termed kiss and run neurotransmitter release

Neurotransmitter release 3

neurotransmitter crosses the synaptic cleft and binds to receptors on the postsynaptic side

Neurotransmitter release 4

near the active zone there are voltage-gated Ca++ channels

Neurotransmitter release 5

Although the presynaptic terminals are the main site of transmitter release, as you will see, the same mechanism can also be used by some neurons to release transmitters from the dendrites or the cell body

How do we now Ca++ is critical in the release of neurotransmitter?

1. if the neuron is bathed in a low Ca++ solution there is still a normal action potential but no neurotransmitter is released \-- demonstrates that Ca++ is necessary for the release of neurotransmitter

2. if Ca++ is directly infused into the terminal, neurotransmitter is released without an action potential \-- demonstrates that Ca++ is sufficient for the release of neurotransmitter

Peptide neurotransmitters are released from secretory granules

1. There are no voltage-gated Ca++ channels near the secretory granules

2. Only a rapid barrage of many action potentials arriving at the terminal will open Ca++ channels long enough to allow sufficient Ca++ to enter the terminal to increase the Ca++ concentration near the secretory vesicles enough so that they can merge with the presynaptic membrane and release their peptide transmitter

This existence of both synaptic vesicles and secretory granules allows...

for a differential release of different types of neurotransmitters from a single presynaptic terminal

Four major types of synaptic connections

1. Axo-dendritic
2. Axo-somatic
3. Axo-axonic
4. Dendrodendritic

*there are also bi-directional synapses

Axo-dendritic

presynaptic axon synapses with postsynaptic dendrite

Axo-somatic

presynaptic axon synapses with postsynaptic soma

Axo-axonic

an axon synapses another axon

Dendrodendritic

A dendrite synapses with another dendrite

Presynaptic inhibition and facilitation

IPSP \= PS inhibition
EPSP \= PS facilitation

Presynaptic facilitation enhances the release of neurotransmitter from the terminal receiving the presynaptic input

therefore the EPSP or IPSP in the postsynaptic neuron is increased

Excitatory input from the terminal producing presynaptic facilitation increases the amplitude and/or duration of the action potential in the recipient "big" terminal

that opens more voltage gated calcium channels, producing an increase in neurotransmitter release from the big terminal

Presynaptic inhibition decreases (or inhibits) the release of neurotransmitter by the big terminal receiving the presynaptic input

Therefore the EPSP or IPSP in the postsynaptic neuron is decreased

Inhibitory input from the presynaptic terminal decreases the amplitude and/or duration of the action potential in the recipient terminal

Because fewer voltage gated calcium are opened, this results in a decrease in neurotransmitter release

The utility (or advantage) of axo-axonic synapses resulting in presynaptic inhibition or facilitation is

that it is a mechanism for enhancing the specificity of a particular input without affecting the other inputs

For review:

a key component of chemical synapses is the synaptic vesicle with neurotransmitter \-- the neurotransmitter is released into the synaptic cleft and binds to receptors in the postsynaptic membrane which results in a postsynaptic potential


there is a 0.2ms synaptic delay in this process, which is the time between the action potential reaching the terminal to the time of a postsynaptic effect

Electrical synapses

1. connexins are particular protein subunits \-- six of the subunits combine to form a channel called a connexon (two connexons pair to form a gap junction, a large pore that bridges between two neurons

2. These neurons are electrically coupled so they almost act as one, bc current and small molecules can easily flow both ways (thus electrical synapses produce neurons that are both electrically and biochemically coupled)

One advantage of electrical synapses

is that they are much faster than chemical synapses bc there is no synaptic delay

Some examples of electrical synapses

1. some circuits (such as those involved with escape behavior) employ electrical synapses bc they are faster than chemical synapses

2. there are dendrodendritic connections that are electrically coupled \-- the electrically coupled neurons tend to act as a single neuron (ie. the tend to generate action potential synchronously bc if one depolarizes, they all depolarize, which will increase their effect of the postsynaptic membrane

3. the pore formed by the connexons can open and close so that these cells can act like a single unit or as individuals \-- results in a lot of flexibility

Why are most synapses chemical?

1. The reason is that a chemical input can be both excitatory and inhibitory (it is a more flexible system)

2. The other reason is that chemical synapses are more plastic than electrical synapses which is probably important for learning

Spontaneously active neurons

a. spontaneously active neurons are neurons that can generate action potentials in the absence of synaptic input

The evidence for the existence of spontaneously active neurons is that in culture (single neuron in a dish)

some types of neuron will continue to fire \--- in that situation there cannot be any synaptic input to that neuron

The rate of action potentials from a spontaneously active neuron can be regulated by synaptic inout

for example, input may increase the rate of action potentials and an inhibitory input may decrease the rate of action potentials

A turtle heart in a dish will beat spontaneously

a. if norepinephrine (a neurotransmitter) is added to the dish, heart rate will increase
b. if acetylcholine (a neurotransmitter) is added to the dish, the heart rate will decrease

In our bodies, the release of norepinephrine from sympathetic neurons increases the heart rate

and acetylcholine from parasympathetic neurons decreases the heart rate

The implications of the existence of spontaneously active neurons range from the cellular level to the philosophical level because...

1. stimulus-response paradigm stated that an organism acts only after a stimulus acts on that organism to evoke a response

2. we now know that organisms can generate their own activity \-- stimulation isn't needed to get a response (ie. dreams and hallucinations)

Mechanisms for the production of spontaneous activity

1. the mechanisms are very complex, involving more than 10 types of ion channels

2. an example is the slow ramp depolarization toward threshold \--- could be caused by a slow progressive closing of K+ leak channels which would progressively depolarize the membrane potential towards threshold or the ramp potential could be caused by a slow progressive opening of Na+ channels which would also depolarize the membrane

Major point:

Not all neurons are created equal \-- they have different personalities (the compliment of voltage gated channels in the membrane gives the neuron its personality)

Mechanisms producing complex PSPs 1:

each of the 4 components of the complex PSP is produced by a different receptor subtype

Mechanisms producing complex PSPs 2:

each of the 4 receptor subtypes would be given a different name

--\> first part of the name is usually the transmitter it binds (ie. glutatmate) followed by R for receptor and then a numerical subscript (ex: gluR1, or YR1 - y\=neuropeptide)

Mechanisms producing complex PSPs 3: the most important point is

It is not the neurotransmitter that produces the EPSP or IPSP rather the effect of the neurotransmitter is produced by the receptor subtype that binds it

(many transmitters produce EPSP by binding one receptor type and IPSP by binding a different receptor subtype)

Mechanisms producing complex PSPs 5:

how fast receptors open and how long they stay open depends on receptor kinetics

Neurotransmitters

a neurotransmitter is a chemical released by neurons in response to depolarization, which produces an effect on another neuron

Peptide neurotransmitters

1. they are chains of amino acids (defining characteristics of a peptide)

2. they are synthesized solely in the soma of neurons

3. they are released from secretory granules

An example of some peptide neurotransmitters

a. opiate transmitters (they bind to the same receptors as morphine)

b. neuropeptide Y (NPY)

Opiate transmitters

1. Enkephalins
2. Endorphins

Neuropeptide Y (NPY)

1. NPY is the most abundant peptide transmitter in the brain

2. it is made up of 36 amino acids and thus is one of the larger peptide transmitters

3. NPY stimulates feeding behavior in some areas of the brain

Non-peptide neurotransmitters

1. non-peptide neurotransmitters are smaller than peptide neurotransmitters

2. non-peptide neurotransmitters can be synthesized in the soma or in the terminal

Some examples of non-peptide neurotransmitters

a. amino acid transmitters
b. catacholamines
c. acetylcholine
d. serotonin
e. ATP
f. Nitric oxide

a. Amino acid transmitters

1. glutamate (the primary excitatory neurotransmitter in the mammalian brain)

2. gamma-amino-butyric-acid (GABA: the primary inhibitory transmitter found in the mammalian forebrain)

3. Glycine (an inhibitory transmitter found mostly in the spinal cord)

b. catacholamines

1. Dopamine (DA)
2. Norepinephrine (NE)
3. Epinephrine (E - also a hormone)

c. Acetylcholine

ACh: the neurotransmitter released at the neuromuscular junction to produce muscle contractions (in contrast it inhibits heart rate)

d. Serotonin

5-HT: acts on 14 known receptors subtypes, the most of any known neurotransmitter \-- considered an inhibitory neurotransmitter

e. ATP

used as a cellular source of energy

f. Nitric oxide

NO: a gaseous molecule that can thus diffuse through the neural membrane \-- can be synthesized in the soma and diffuse back to a presynaptic terminal

The common steps in synaptic transmission

1. the release of neurotransmitter from the presynaptic terminal

2. the binding of the neurotransmitter to postsynaptic receptors

3. inactivation of the neurotransmitter

4. the reuptake of the synaptic vesicle

5. synthesis (or resynthesis) of neurotransmitter

two types of receptors

the ion channels and the metabotropic receptors

--\> opening ion channels has an electrical effect (changes membrane potential)
--\> activation of metabotropic receptors (also known as G-protein linked receptors or second-messenger linked receptors) changes cell biochemistry

inactivation of the neurotransmitter

1. many neurotransmitter actions should be brief (inactivation mechanisms are needed to make this possible)

2. one mechanism of inactivation is simply the diffusion of the neurotransmitter away from the synaptic cleft

3. another mechanism of inactivation is enzymatic degradation of the neurotransmitter molecules

4. a third mechanism of inactivation is transporters that pump the neurotransmitter away from the synaptic cleft (transporters can pump the neurotransmitter back into the presynaptic terminal or into astrocytes

Drug that affect neurotransmitter release

1. tetrodotoxin (TTX) block voltage-gated Na+ channels preventing action potentials (all neurotransmitter release is blocked)

2. Amphetamine increases the release of dopamine (DA) and norepinephrine (NE)

Drugs that affect receptors

1. Agonists are drugs that bind to a receptor and mimic the effect of the neurotransmitter (they are frequently more specific than the neurotransmitter)

2. Antagonists are drugs that bind to receptors to receptors and block their activity

Agonists

Morphine activates opiate receptors

Antagonists

a. Nalaxone blocks opiate receptors

b. Curare blocks nicotinic acetylcholine receptors (the acetylcholine receptor subtype that is expressed in skeletal muscle) and this causes paralysis

c. Atropine block muscarinic acetylcholine receptors

d. Haloperidol block DA receptors

Drugs that affect enzymatic degradation

1. Nerve gas blocks acetylcholinesterase \--- there is an increase synaptic concentration of ACh which causes respiratory paralysis (by overstimulating diaphragm) and also reduced heart rate

\---\> atropine is an antidote for nerve gas