Chapter 3 : Neurotransmission
Drugs for Alzheimer's disease alter acetylcholine Neurotransmission
Early Alzheimer's disease (AD), a neurobiological illness characterized by a progressive decline
in cognitive function.
Acetylcholine inhibitor, a drug that enhances levels of a neurotransmitter called acetylcholine in
the brain. Note: this drug is usually given to patient with Alzheimer's to help slow down the
Most neurobiological disorders address neurotransmission abnormalities in the nervous system,
though not all of the drug treatments work and new treatments need to be created
Electrical events within a neuron and the release of neurotransmitters
Neurotransmission :- the transmission of information between neurons.
- it involves a neuron releasing neurotransmitters into a synapse, which allows for these
released neurotransmitters to act on sites of another neuron.
- the study of neurotransmission involves:
looking at the events inside the neuron that causes the production and release of
the actions of neurotransmitters on sites situated on other neurons
Electrical transmission :- series of electrical events that begin at an axon hillock and proceed
down the length of an axon and they depend on electrical potentials.** occurs before a
neurotransmitter in released.
Electrical potential :- the difference between the electrical charge within a neuron and the
electrical charge of the environment immediately outside the neuron.
- The electrical charge within a neuron is negative compared to the outside environment in
- This particular characteristic keeps the neuron's membrane polarized :- keeping one side of the
membrane negative, while the other side is positive Note: Fig 3.1
Depolarization :- a reduced difference between the positive and negative charges on each side of
the membrane. Ex: going from -70 mV to -20 mV Hyperpolarization :- an increased difference between the positive and negative charges on each
side of a membrane.
REVIEW : a neuron has many dendrites and a single axon. A single synapse consists of an axon
terminal, the synaptic cleft and the postsynaptic terminal.
Local potential :-an electrical potential on a specific part of a neuron.
- local potential changes in response to events within a neuron and with communication from
- local potential change as charged particles move in and out of the ion channels.
Ion channels :- pores in a neuronal membrane that allow the passage of charged particles called
ions to move in and out of the neurons through pores
Excitatory postsynaptic potential (EPSP) :- depolarizes a local potential.
Inhibitory postsynaptic potential (IPSP) :- hyperpolarizes a local potential
- The influences of other neurons on the local potential occurs as either EPSP or IPSP
Note :-Fig 3.2
box 3.1 Electrophysiology and Microdialysis
Electrophysiology :- a research technique that uses electrodes to measure potential on neuronal
- An electrophysiology either produces macroelectrodes or microelectrodes
Macroelectrodes :- record the activity of thousands of neurons within a structure.
- They can also be used as a stimulator to activate thousands of neurons within a structure.
Microelectrodes :- provide a precise assessment of either just a few or even single neurons.
Intracellular :- the use of a microelectrode to measure potentials within a single neuron.
- used by researchers to measure action potential
- this technique allows a neuron's firing rate to be calculated Note: Electrophysiology cannot determine the amount of neurotransmitter released from a
neuron, it can only asses the activity of the neurons.
Microdialysis procedures :- can be used to sample neurotransmitter levels.
- Microdialysis probes have a semi-permeable membrane
- when it is implanted into a structure of the brain, a probe's membrane allows some of the
surrounding cerebrospinal fluid(CSF) to pass through.
-Researchers then analyze the collected CSF for levels of certain chemicals such as
- the probe size limits neurotransmitter detection to an entire structure rather than a specific
- Increases in neurotransmission must be large enough to cause neurotransmitters to cause
significant overflow from synapses
Similarities and differences between Electrophysiology & Microdialysis
- Microdialysis procedures lack the precision since it detects the entire structure where as the
electrophysiology has more precision
- Though Microdialysis can answer important questions about neurotransmitter release that
- Both of these procedures complement each other and the following study done by Ishida and
colleagues(2005) show that.
Ishida and colleagues(2005) study
- In this study, the effects of β-phenylethylamine(β-PEA) on dopamine neuron firing rates and
dopamine release was assessed in rats.
- the application of β-PEAonto dopamine neurons in the ventral tegmental area caused a
decrease in firing rates as determined through electrophysiology (Note: Fig 1)
- Where as the Microdialysis showed an increased dopamine release (Note: Fig 2)
- Based on these findings and other infos. known about β-PEA, the authors concluded that
increases in dopamine release were caused by β-PEA acting at dopamine D2 auto receptors.
Nerve impulses: electrical potential changes in neurons Nerve impulses :- An important way in which neurons release neurotransmitters from axon
terminal is through electrochemical signals called nerve impulses
- they are comprised of changes from resting potential to action potential
Resting potential :- describes a negatively charges local potential that precedes an action
- Exact negative charge of resting potential can vary between species, nervous system structure
and the relative concentration of ions within and outside a neuron
Note: Fig 3.3
Ex: Squid has -70 mV resting potential
- The resting potential exist because negatively charged proteins within the neuron and closed
ion channels prevent the entrance of positively charged ion like sodium
- Channels are open for the positively charged ion potassium
- Although, the influx of potassium alone is insufficient to affect the resting potential charge
Electrostatic attraction :- Positively charged ions enter the neuron because they are attracted to
the negative charge within the neuron. The attraction of ions with opposite charges.
Concentration gradient :- At some point, K+ cease entering the neuron because ions of the
same type K+ becomes more concentrated within the neuron, hence some k+ follow
a concentration gradient and exit the neuron. Particles of the same type resist being concentrated
The balance between electrostatic attraction and concentration-gradient repulsion facilitates a
- During resting potential, Na+ channels are not open; though a number of Na+ still find their
way to enter the channels
- To prevent the excess entrance of Na+, neurons contain a sodium-potassium pump
Sodium-potassium pump :- a neuronal membrane mechanism that brings two K+ ions into the
neuron while removing three Na+ ions out of the neuron (Note: Fig 3.4)
- By removing more Na+ ions than K+ ions brought in, this pumping activity results in a net
- the resting potential changes when Na+ channels open - Na+ channels are voltage-gated ion channels
Voltage-gated ion channels :- the opening or closing of these channels depends on local
- Na+ channels open in response to depolarization i
-When an EPSP occurs, depolarization causes local Na+ channels to open, allowing Na+ ions to
enter the neuron.
- If no further EPSP takes place, then the depolarization quickly ends and a resting potential
-Combined EPSP produces greater depolarization :
1) Several EPSPs may produce temporal summation :- short succession of EPSP from the same
2) Several EPSP may occur simultaneously from multiple sources called spatial summation
- If a series of EPSPs causes depolarization to reach a certain threshold value, then an action
potential will occur.
Action potential :- is a rapid depolarization that causes the potential in the neuron to become
temporarily more positive than the outside environment (Note: Fig 3.5)
- Action potentials occurs when all Na+ ion channels OPEN
- These Na+ ion channels stay open for 1 to 3 milliseconds, limits the change in potential to a
All-or-none law :- the magnitude of an action potential is independent from the magnitude of
potential change that elicited the action potential.
- Action potential ends immediately after the Na+ channels close.
- Refractory period begins after the action potential ends (Note: Fig 3.5)
Refractory period :- the neuron resists producing another action potential.
- There are two phases of refractory period :
1.Absolute refractory period :- which lasts approximately 1-2 milliseconds after the action
potential ends. - During theARP period, K+ channels are opened and the concentration of positively charged
ions causes K+ ions to rapidly exit the neuron
- The rapid exit of K+ ions causes the potential to become negative again
- Due to Na+ channels remaining closed during absolute refractory period, no amount of
depolarization can produce another action potential
2.Relative refractory period :- second phase of refractory period, during which greater
depolarization is necessary to reach threshold and produce another action potential
- this lasts 2-4 milliseconds
- Na+ channels can be opened and the local potential remains hyperpolarized
- because of hyperpolarization, greater depolarization is required to reach a threshold to produce
another action potential
- Unless EPSP occurs during the relative refractory period, the membrane returns to a resting
Propagation of action potentials down axons
Propagation of action potential :- a series of action potential occurring in succession down an
- it all begins at the axon hillock.
- Once this begins, each depolarization produced by an action potential causes another action
potential to occur further down the axon (Note: Fig 3.6)
- These series of action potentials continues until an action potential occurs at the axon terminal
- Action potentials are unidirectional because preceding portion of an axon is in refractory period
- Myelin sheathing increases the speed of conductance down the axon
Nodes of ranvier :- the uncovered sections of axon between myelin sheath
- Each nodes contain a Na+ and K+ channels
- when Action potentials occur at one node, depolarization is carried through the myelin
sheathing to the next node - the jumping of action potential from one node to another is referred as saltatory conduction.
- the number of action potentials occurring per unit of time (milliseconds) is called firing rate.
Neurotransmitters: signaling molecules for neuronal communication
Neurotransmitter :- are signaling chemicals that are synthesized within neurons, are released
from neurons, and have effects on neurons or other cells.
- Action potential at an axon terminal triggers a series of events, which leads to release of
- there are a series of stages involved in neurotransmission, beginning with the synthesis of
neurotransmitters and ending with the release of neurotransmitters (Note: Fig 3.8)
- Neurotransmitters are synthesized from other molecules with the aid of enzymes
- Smaller neurotransmitter molecules such as acetylcholine and dopamine are synthesized in the
-Larger neurotransmitter molecules such as neuropeptide neurotransmitters are synthesized in the
- once the neurotransmitters are synthesized, they are stored in protective vesicles.
Vesicular transporter :- channel located on a vesicle that allows passage of neurotransmitters.
- These synaptic vesicles prevent neurotransmitters from being destroyed by enzymes
- Synaptic vesicles prevent neurotransmitters from being released prematurely
- They also allow neurotransmitters to be pooled in the axon terminal
- Allows for immediate neurotransmitter release during neurotransmission
- Though not all neurotransmitter is stored after synthesis. Ex: Endocannabinoid (anandamide)
neurotransmitter is not stored in vesicles
Immediately after synthesized, anandamide escapes from the neuron Calcium influx and neurotransmitter release
- Voltage-gated calcium channels open and allow Ca2+ to enter the axon terminal once an action
potential entered the axon terminal.
- Ca2+ causes exocytosis
Exocytosis :- the fusing of synaptic vesicles to the axon membrane and release of stored
neurotransmitters into the synaptic cleft
- once fused with the membrane, the vesicles are brought back into the terminal and refilled with
- Note: there are no recycling of vesicles for neuropeptide neurotransmitters; they must be stored
in the vesicles produced in the soma instead
Neurotransmitters bind to receptors
- Neurotransmitters released into the synaptic cleft bind to receptor proteins, which may be
located on the post synaptic terminal, axon terminal or both
Volume neurotransmission :- type of neurotransmission involving the binding of
neurotransmitters to receptors outside of the synapse
- Volume transmission occurs from the overflow of neurotransmitters from a synaptic cleft,
which generally results from high neuronal activity.
Termination of neurotransmission
- Two different processes takes place once a neurotransmitter releases from a receptor and they
serve to end neurotransmission:
1. Catabolism :- enzyme breaks down a neurotransmitter into different molecules
- Once broken by enzymes, they can no longer match the receptor sites and the
neurotransmission is stopped
2. Reuptake :- transporter channels on axon terminals return neurotransmitters to the axon
- vesicles store these for later release
- reuptakes serves as a recycling program for neurons
3. Neurotransmitters can also leave the synaptic cleft and go into an astrocyte glial cell
- enzymes within the glial cell catabolizes the neurotransmitters Neurotransmission: Neurotransmitter binding to receptors
- Receptors are proteins located in neuron membranes that can be bound to and activated by
- Receptors match to a specific neurotransmitter
- Researchers characterize receptors by:
a. the neurotransmitters they match to
b. their location within a synapse
c. the basic molecular structure
Pre-synaptic receptors :- receptors located on the axon terminal
- Pre-synaptic receptors have two types : (Note: Fig 3.9)
1. Autoreceptor :- a presynaptic receptor that is activated by neurotransmitters released from the
same axon terminal
- activating autoreceptors, usually inhibits neurotransmitter release
Ex: a receptor for dopamine functions like an autoreceptor, when released dopamine from an
axon terminal, the dopa neurotransmitter will go and bind to this autoreceptor, which will reduce
the amount of dopamine released
2. Heteroreceptor :- a presynaptic receptor that is activated by neurotransmitters diffrent from
those released from the axon terminal
- Heteroreceptor may increase or decrease neurotransmitter release
Ex: a receptor for norepinephrine functions like Heteroreceptor, which is located on axon
terminals for the neurotransmitter serotonin, once bonded to this receptor, reduces the serotonin
Post-synaptic receptors :- receptors located on the post synaptic terminal
Receptors: Ionotropic or Metabotropic (Note: Table 3.1 for differences)
Ionotropic receptors :- in channels that open when a matching neurotransmitter binds to a site
on the channel (Note: Fig 3.10)
- Ionotropic receptors are comprised of subunits that span the neuronal membrane
- the subunits form a ring that comprises the channel - the shifting of these subunits cause the channel to open or close
- Ionotropic receptors contain ion channels
Metabotropic :- physically separated from parts of the neurons where the receptor exerts its
effects (Note: Fig 3.11)
- Metabotropic receptors relies on a G-protein to convey effects to channels or other parts of the
G-protein :- a G-protein resides within a neuron in close proximity to the receptor
- G-protein has three subunits : alpha, beta and gamma
- The three subunits of G-protein remain attached to each other, until a neurotransmitter activates
- Once G-protein activates, it splits into two sections:
a. consists of the alpha subunit only
b. consists of the beta and gamma subunits together
- After a period of time, the subunits come back together again
- the separated subunits may causes variety of effects within a neuron
1. the free subunits can activate ion channels such a K+ or Ca 2+ ion channels
2. the free subunits can activate effector enzymes:- enzyme that usually activates a second
- Common effector enzymes are : adenylyl cyclase, phospholipaseC, phospholipaseA2, and
- Common second messengers include cyclic Adenosine monophosphate, cyclic guanosine
monophosphate, phosphinositide and calcium
Second messenger :- activates a protein kinase
Protein kinase :- an enzyme that causes phosphorylation of a substrate protein/ activating a
- Phosphorylation is a common process for activating protein , which involves at least one
phosphate group to a protein
- Common protein kinase include protein kinase A, protein kinase G, protein kinase C and
calcium/calmodulin kinase Substrate protein :- can be an ion channel, an enzyme involved in making of neurotransmitters,
a neurotransmitter receptor or other proteins within the neuron or can also be a transcription
- two common transcription factor for neurons are c-Fos and cAMP response element-binding
- Also the activation of genes may lead to the synthesis of proteins within the neuron, including
receptors for neurotransmitters and enzymes used in neurotransmitter synthesis
Review: a transcription factor activates or deactivates a gene
Different types of neurotransmitters and communication
Note: table 3.2
Glutamate and GABAare the most abundant neurotransmitters
- the amino acids glutamate and GABA are found throughout the nervous system
- The amino acid neurotransmitter glutamate is the most prominent member of a small amino
acid family called excitatory amino acid neurotransmitters
- The amino acid GABAis the most prominent member of a small amino acid family called
inhibitory amino acid neurotransmitters
Glutamate :- is synthesized within the axon terminals from the amino acid glutamine
- The enzyme glutaminase converts glutamine to glutamate (Note Fig 3.12)
- After synthesis, vesicular transporters carry glutamate into protective vesicles, where it resides
for later release into the synapse
- Glutamate is released from pyramidal neurons
- Within the synaptic cleft, glutamate binds to any of four types of receptors:
a. Ionotropic - NMDA, AMPA, Kainite receptors
b. Metabotropic - mGlu receptor
- When activated, the ionotropic NMDA,AMPAand Kainite receptors allow positively charged
ions to enter a neuron (Note Fig 3.13)
- The influx of positively charged ions function as excitatory post synaptic potentials RECEPTORS
- NMDAstands for N-methyl-D-asparatate, which is a drug that serves as a agonist, a drug that
mimics neurotransmitter, at these receptor
- AMPAstands for α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic