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320 Cards in this Set

  • Front
  • Back
What was Camillo Golgi's contribution to the study of neuroscience? What did it allow?
He devised a way to stain neurons with silver salts. This allowed scientists to view their entire structure under the microscopes.
What is the neuron doctrine? Who proposed it?
Santiago Ramon Y Cajal proposed the neuron doctrine. This is the principle that individual neurons are the elementary signaling elements of the nervous system.
What is meant by "dominant hemisphere"? How does it relate to language?
The dominant hemisphere is the hemisphere that is connected to the dominant hand. It also controls speech.
Many left-handed people have a dominant left hemisphere, but most right-hemisphere-dominant people are left-handed.
How many neurons are there in the human brain?
10^11 neurons
How many different neuronal types are there?
1,000 different types
What is the key organizational principle of the brain?
Nerve cells with basically similar properties can produce quite different actions because of the way they are connected with each other and with sensory receptors.
What are the main two classes of cells in the nervous system.
neurons and glia
What are the 8 general functions of glia?
1. structural support
2. insulation, via the production of myelin
3. remove debris after injury or neuronal death
4. housekeeping chores, such as the reuptake of neurotransmitters
5. guide migrating neurons and direct the outgrowth of axons
6. regulate properties of presynaptic terminal at the nerve-muscle synapse
7. help to form blood-brain barrier
8. release growth factors to nourish nerve cells
What are the two major classes of glia?
microglia and macroglia
What is the origin of microglia?
They arise from macrophages outside of the nervous system and become activated during infection, injury, and seizures.
What do activated microglia do?
They are phagocytotic and express a range of antigens. They are perhaps the major APC of the CNS.
What are the 3 types of macroglia?
Oligodendrocytes, Schwann cells, and astrocytes
What is the function of oligodendrocytes?
They provide a myelin sheath to a few (about 15) different axon internodes in its vicinity.
What is the function of Schwann cells?
They provide a myelin sheath but only to one axon internode.
What is the function of astrocytes?
Their main function is structural support.
Those with endfeet on nerve cell bodies supply the nerve cell with nutrients.
Those with endfeet on the brain's capillaries form the blood-brain barrier.
They also take up excess K+ and neurotransmitters.
What are the four morphologically defined regions of a neuron?
Soma, dendrites, axons, and presynaptic terminals
What is the function of a soma?
It contains the nucleus and is the metabolic center and main protein synthesis location.
What is the function of a dendrite?
Receives incoming signals in a graded fashion
What is the function of an axon?
It carries electrical signals in an all-or-nothing fashion.
What is the function of presynaptic terminals?
They are the swollen ends of the axons that store neurotransmitter to be released into the synaptic cleft.
What are the 4 functional components of neuronal cells? Is the signal characteristic of each component electrical or chemical?
Input component - electrical
Integrative/trigger component - electrical
Conductile component - electrical
Output component - chemical
What does "resting membrane potential" mean?
the difference in electrical potential between the inside and the outside of the plasma membrane
What is the typical resting potential of a neuronal cell?
-65 mV, but it can range from -40 mV to -80 mV
Define "depolarization".
a reduction in membrane potential
Define "hyperpolarization".
an increase in membrane potential and makes the cell less likely to generate an action potential
What is the type of electrical signal produced in axons?
action potentials
Compare and contrast the features of an action potential with those of a graded potential such as a receptor or synaptic potential.
Both are electrical signals.
Graded potentials can hyperpolarize or depolarize while action potentials only depolarize.
Action potentials have much larger amplitudes than graded potentials.
Action potentials are stereotyped in that they vary little along an axon and from one neuron to another. Graded potentials vary in amplitude, duration, and long distances.
Where is the trigger region of an axon?
the axon hillock or the first node of Ranvier
How far can an action potential be conducted along an axon?
3 m
How far do signals such as receptor or synaptic potentials spread from their point of origin?
1 - 2 mm
Relate the terms "excitatory" and "inhibitory" to "depolarization" and "hyperpolarization".
Depolarization is an excitatory stimulus
Hyperpolarization is an inhibitory stimulus
Finish the following sentence: "The information conveyed by an action potential is determined not by..."
...the magnitude or duration of individual action potentials, but by their frequency.
What is the function of myelin?
It insulates axons and facilitates quicker conduction of the action potentials.
What kind of information is conveyed by the action potential firing frequency of a neuron?
intensity of the sensation or the speed of the movement
Define "synapse".
The junction and related structures that conveys a signal from one neuron to another.
Define "presynaptic cell".
The cell participating in a synapse which carries the signal to be transduced.
Define "postsynaptic cell".
The cell that receives the signal.
Define "presynaptic terminal".
The swelling that contains the neurotransmitter at the end of the presynaptic axon.
Define "synaptic cleft".
The space between the cells at a synapse.
Describe unipolar cells and give an example.
They have a single process that has different branches that serve as receptive surfaces and releasing terminals. They are found in invertebrate nervous systems and the human autonomic system.
Describe bipolar cells and give examples.
They have two processes (a dendrite and an axon) that are functionally specialized. They are found in the retina and olfactory epithelium.
Describe pseudo-unipolar cells and give examples.
They develop as bipolar cells but the processes fuse relative to the cell body. These cells include most peripheral sensory neurons.
Describe the multipolar cells.
They have an axon and numerous dendrite process with much variance. They are the most common neuron in the mammalian nervous system.
Draw and label the structures that play a role in the knee jerk (stretch) reflex.
See page 1 of Neurophysio notes.
List the steps of what happens when the knee jerk reflex is elicited by tapping the patellar tendon.
1. The patellar tendon is tapped.
2. This stretches the quad m, including the muscle spindle.
3. The muscle spindle afferent activates the extensor motor neuron and the inhibitory interneuron.
4. The extensor motor neuron causes the quad m to contract
5. The inhibitory interneuron inhibits the flexor motor neuron.
6. This prevents any contraction in the hamstring muscles.
What are the 4 kinds of information conveyed by the stretch reflex?
1. Sensory information from the body's surface to the CNS.
2. Motor commands from the CNS to the muscles.
3. Complementary inhibitory commands to opposing muscles.
4. Ascending info for coordination.
Define divergence, describe its functional significance, and state where it occurs in the nervous system.
When one source of input branches out to multiple output connections. It allows a single neuron to have wide and diverse influence. This is typical of input systems (sensory).
Define convergence, describe its functional significance, and state where it occurs in the nervous system.
When multiple sources of input act on one target cell. It allows the target cell to integrate diverse information from multiple sources. This is typical of motor systems.
Why is the stretch reflex called a monosynaptic reflex?
The sensory neuron and the motor neuron exerting the action are directly connected, so there is only one synapse involved.
What is a spinal reflex?
A reflex that is entirely mediated by cells within the spinal cord.
What is feedforward inhibition?
The simultaneous activation of one effector and inhibition of another. In the knee-jerk reflex, the afferent neurons from the extensor muscles excite both the leg extensor motor neurons and inhibitory neurons that prevent the firing of the leg flexor motor neurons. It enhances the effect of the active pathway by suppressing the activity of the other, opposing, pathways.
What is feedback inhibition?
A self-regulating mechanism in which the extensor afferent neurons act on inhibitory interneurons, which feed back to the extensor motor neurons themselves and thus reduce the probability of firing by these cells. The effect is to dampen activity within the stimulated pathway and prevent it from exceeding a certain critical maximum.
What is known about the influence of the serotonin 1B receptor on aggressive behavior?
A lack of serotonin 1B receptors increases aggressive behavior.
Low concentration of serotonin has been linked to increased aggressiveness.
However, increased levels of serotonin have also been associated with aggression. These studies are not contradictory; rather they demonstrate that the relationship is complex.
What is known about the relationship between novelty-seeking behavior and the D4 dopamine receptor?
Polymorphisms in the gene encoding the D4 dopamine receptor correlate with novelty-seeking behavior.
What are the four features of Huntington's disease?
Heritability
Chorea
Cognitive impairment
Death
What is the frequency of Huntington's disease?
Affects both men and women with a frequency of 5 per 100,000.
What is the fate of persons with Huntington's disease?
Death within 15-20 years.
Is Huntington's disease a monogenic or a multigenic disorder?
monogenic
What is the relationship of trinucleotide expansion and genetic anticipation to Huntington's chorea?
Increased trinucleotide repeats results in earlier onset, and repeats tend to expand paternally from generation to generation (this is termed anticipation).
What are 3 examples of diseases in which trinucleotide expansion plays a role, other than Huntington's disease?
Myotonic dystrophy, Fragile X mental retardation, Spinocerebellar ataxia
What 5 diseases/conditions are considered to be multigenic disorders?
Diabetes, coronary artery disease, asthma, manic-depressive disorder, and schizophrenia
What are the two features of neurons that distinguish them from most other cells?
Neurons are highly polarized and functions are compartmentalized to a high degree.
What kinds of cells, other than neurons, have polarity?
Epithelial cells and other non-neuronal secretory cells
What kind of cells, other than neurons, have excitability?
Muscle cells
What is the basis for the different neuronal types?
The different neuronal types result from developmental differentiation and are based on the macromolecules that the neuron produces.
What organelles are found in the soma of a neuron?
Nucleus, RER, ribosomes, golgi, lysosomes, mitochondria, SER
What organelles are found in the dendrites?
Mitochondria and SER
Also, RER, ribosomes, golgi, and lysosomes are found but diminish as you move away from the soma.
What organelles are found in axons?
Synaptic vesicles
What are the three filamentous structures that compose the cytoskeleton?
Microtubules, neurofilaments, and actin microfilaments
Where are the filamentous structure of the neuron found?
Microtubules: full length of neuron
Neurofilaments: abundant in axons
Actin mircofilaments: cell periphery
What are the diameters of the filamentous cytoskeletal structures of the neuron?
Microtubule: 25-28 nm
Neurofilament: 10 nm
Actin microfilament: 3-5 nm
What are the basic subunits of the filamentous cytoskeletal structures of the neuron?
Microtubules: alpha- and beta-tubulin heterodimer
Neurofilaments: N/A
Actin microfilaments: (G) actin monomers
How stable are the filamentous cytoskeletal structures of the neuron?
Microtubles are low in dividing cells and high in mature processes; their stability comes from MAPs.
Neurofilaments are very stable and almost totally polymerized.
Actin microfilament stability depends on binding proteins; they are constantly growing and shortening.
What is the main function of the filamentous cytoskeletal structures of the neuron?
Microtubules develop and maintain processes and serve as a track for transport.
Neurofilaments are the "bones" of the cytoskeleton.
Actin microfilaments interact with proteins in the periphery and serve as a track for transport.
In the stretch reflex, where is the soma of the sensory neuron?
dorsal root ganglion
In the stretch reflex, where is the soma of the motor neuron?
ventral horn gray
In the stretch reflex, what does the sensory neuron axon contact?
(central) motor dendrite and soma
In the stretch reflex, what does the motor neuron axon contact?
muscle fibers
(some recurrent axons contact the cells own soma)
In the stretch reflex, what does the sensory neuron release?
L-glutamate
In the stretch reflex, is the sensory neuron excitatory or inhibitory?
Excitatory
In the stretch reflex, what does the motor neuron release?
Acetylcholine
(L-glycine if the axon is recurrent)
In the stretch reflex, is the motor neuron excitatory or inhibitory?
Excitatory
(inhibitory if the axon is recurrent)
What are dendritic spines?
short, specialized dendritic extensions that increase the receptive area
What is a homonymous muscle?
The muscle in the stretch reflex that contains the sensory muscle spindle
What is a synergistic muscle?
The muscle in the stretch reflex with cooperative movements to the homonymous muscle
What is the axon hillock?
The unmyelinated base of an axon where the cytoplasm changes and the trigger zone is located
What is the synaptic bouton?
The knob-like terminals of the axons of presynaptic neurons
What is the trigger zone?
The site where incoming signals are integrated and the action potential is generated
What is a motor unit?
A motor axon and all the muscle fibers it innervates
What is the function of myelin?
It insulates axons to increase the speed of signal transduction
How does myelination of an axon occur?
Shwann cells line up along the axon at intervals that will eventually become the nodes of Ranvier. The external cell membrane of each Schwann cell surrounds a single axon and forms a double-membrane structure called the mesaxon which elongates and spirals around the axon in concentric layers. The cytoplasm of the Schwann cell is squeezed out during the ensheathing process when the Schwann cell's processes condense into the compact lamellae of the mature myelin sheath.
What is a node of Ranvier?
A short length of non-myelinated axon between myelin sheaths
What glial cells myelinate the CNS and PNS?
CNS: oligodendrocytes
PNS: Schwann cells
How many axons are myelinated by a single Schwann cell? By a single oligodendrocyte?
Schwann cells: one internode of one axon
Oligodendrocytes: one internode of several axons
What causes demyelination in multiple sclerosis?
Myelin basic proteins (MBPs) elicit a strong immune response/allergic reaction that causes local inflammation and destruction of the myelin sheath
What causes demyelination in Charcot-Marie-Tooth disease?
It involves the gene coding PMP22, a Schwann cell protein normally present in compact myelin. The gene is on chromosome 17. The disease results from the duplication and hence over-expression of this gene, resulting in increased production of PMP22.
What particular intracellular transport problem do neuronal cells face?
The distance between the site of protein production (the soma) and protein secretion (axon terminal) can be quite large relative to the neuron. This requires a fast and efficient method of transport.
What are the four categories of fast and slow transport within neurons?
Fast anterograde
Fast retrograde
Slow (slower)
Slow (faster)
What is the rate of transport for the four types of transport in neuronal cells?
Fast anterograde: 400-440 mm/day
Fast retrograde: 200-270 mm/day
Slow (slower): 0.2-2.5 mm/day
Slow (faster): 0.4-5.0 mm/day
What is the direction of slow transport within the neuronal cell?
anterograde only
What structures are transported via fast anterograde transport within neurons?
Various vesicles, mitochondria, and SER elements
Which transport mechanisms are used to transport microtubules within neurons?
Fast retrograde, slow (slower), and possibly slow (faster)
What molecular motors are associated with fast transport within neurons?
Fast anterograde: kinesin and KIFs
Fast retrograde: Microtubule-associated ATPase-1C (MAP-1C)
Which transport mechanims in neural cells require ATP?
Fast anterograde and Fast retrograde
How can the indiscriminate nature of retrograde transport be harmful to a neuron?
Toxins (such as tetanus) and pathogens (such as herpes, rabies, and polio) are transported to the cell body (and therefore the CNS) by fast axonal retrograde transport.
What are the 3 important properties of ion channels?
1) they conduct ions
2) they recognize and select specific ions
3) they open and close in response to specific electrical, mechanical, or chemical signs
What are the 3 classes of gated channels?
1) Voltage-gated channels
2) Ligand-gated channels
3) Mechanically-gated channels (regulated by pressure or stretch)
Compare gated-channels to resting channels.
Resting channels are normally open in the cell at rest and contribute to the resting potential.
Gate channels are usually closed except when stimulated and they disrupt the resting potential.
How are lipids and integral proteins arranged in the cell membrane?
The cell membrane is 6-8 nm thick and formed by a double layer lipid and protein mosaic, which hydrophilic heads of lipids arranged at the exterior and hydrophobic lipid tails to the interior. Integral proteins are embedded into or through the hydrophobic region.
How can ion channels operate as a simple resistor?
The current through a channel varies with membrane potential in a linear fashion, like a resistor.
What is Ohm's law?
i = V/R
What is the relationship between resistance and conductance?
Conductance is the inverse of resistance
What are the units of conductance and resistance?
Conductance: siemens
resistance: ohms
Briefly describe the classes of ion channels in terms of the ions that can permeate them.
Some cation-selective channels allow Na+, K+, Ca2+, and Mg2+ to pass indiscriminately. Other cation-selective channels are only permeable to one type of cation. Most types of anion-selective channels are highly selective and conduct only Cl-.
What causes ions to move through ion channels?
1) the electrical potential difference across the membrane
2) the concentration gradient of the permeant ions across the membrane.
Changing either one can change the net driving force.
What is a rectifier?
A rectifier conducts ions more readily in one direction than the other. The conductance of this channel varies according to the surrounding solution.
Compare the conductance of a rectifying channel with that of a channel that behaves as a simple resistor.
The conductance of a simple resistor-type channel varies in a linear fashion as voltage changes.
The conductance of a rectifying-type channel does not vary in a linear fashion with the same voltage changes, and it can be saturated.
What is "gating"?
the conformation change of an ion channel from an open to a closed state
What are the three physical models of gating?
1) localized conformation change is a change in one region of the channel
2) generalized structural change occurs along the length of the channel
3) a blocking particle is tethered to, and swings in and out of, the channel
What are the four categories of stimuli that control ion channel opening and closing?
1) Ligands. Can bind to either the extracellular or intracellular side.
2) Phosphorylation of phosphorylation-gated channels. Opens them by causing a conformation change, and my occur as a result of intracellular energy changes.
3) Voltage. Change is based on a net presence of basic or acidic amino acids exposed on the surface of an ion channels. The voltage changes cause these amino acids to change their charge and mediate a conformation change in the channel.
4) Stretch or pressure.
What are the 3 functional states of channels?
1) Resting state is closed and activatable
2) Active state is open
3) Refractory state is closed and non-activatable
What is the difference between desensitization and inactivation of an ion channel?
Desensitization occurs when a ligand-gated channel enters the refractory state despite the continued presence of the activating ligand. This may be an intrinsic property of the channel or it might be mediated by phosphorylation by a protein kinase.
Inactivation is the transition to the refractory state from the active state by: 1) voltage-gated channels, 2) an intrinsic subunit of the channel, 3) by a change in the concentration of Ca2+ ions which either directly inactivates the channel or indirectly inactivates it by activating a protein kinase which phosphorylates the channel.
What is the basic structure of an ion channel?
An ion channel is formed from two or more integral glycoprotein subunits (which can be identical or different) that form a pore that spans the width of the membrane.
What are the different types of ion channels as determined by the gene families that encode their proteins?
Ligand-gated channels
Gap junction channels
Voltage-gated channels
Voltage-gated K+ channels
Inward-rectifying K+ channels
Other selective K+ channels
What is the basis for membrane-potential?
The membrane potential results form the separation of net positive and negative charges across the membrane. At rest, a nerve cell has an excess of positive charges outside the membrane and an excess of negative charges inside the membrane. The separation of charge is maintained because the lipid bilayer blocks the diffusion of ions.
Define resting membrane potential.
The resting membrane potential is the membrane potential of the cell at rest.
What is the basis for electrical signaling by cells?
It involves brief changes from the resting membrane potential due to alterations in the flow of electrical current across the cell membrane.
What is current flow?
The net movement of positive charge
Compare and contrast electrotonic and action potentials on the basis of gated ion channel opening.
Electrotonic potentials are changes in membrane potential that do not lead to opening of gated ion channels; they are passive responses of the membrane.
Active potentials are an all-or-none opening of the voltage-gated ion channels in response to a threshold level of depolarization of the membrane.
How do the intracellular/extracellular concentrations and gradients in vertebrate nerve cells compare to those in the giant squid axon?
The absolute values of the ionic concentrations for vertebrate cells are 2-3 times lower than those for the squid giant axon, but concentration gradients (the ratio of the external ion concentration to internal ion concentration) are about the same.
How is the resting membrane potential of a glial cell generated?
The only resting ion channel is the K+ channel. A glial cell has a high concentration of K+ inside the cell. As a result, K+ in the glial cell tends to diffuse from the inside to the outside of the membrane to accumulate a positive charge, while the inside accumulates a negative charge. The potential difference tends to oppose the further efflux of K+. At -75 mV, the electrostatic forces pushing K+ into the cell balance the chemical forces driving K+ out.
What is the K+ equilibrium potential?
The electrical potential at which the elctrostatic driving forces and the chemical driving forces acting on K+ ions are opposite and balanced.
What are the equilibrium potentials for Na+ and Cl-?
Na: 54 mV
Cl: -60 mV
What is the effect on the membrane potential of making the basic glial cell slightly permeable to Na+?
The resting membrane potential will reach a steady value of -60mV when the flux of K+ out and Na+ inward are balanced. The resting membrane potential is closer to the K+ equilibrium potential because of the large number of K+ resting ion channels as compared to the number of Na+ channels.
What is the main role of the Na+/K+ ATPase?
Why is the pump said to be electrogenic?
It mainly prevents the dissipation of the ionic concentration gradients. It is said to be electrogenic because it pumps one more positive charge out than it pumps in per cycle, contributing to the membrane ptoential.
When is the Goldman equation used to determine the membrane potential of a cell (instead of the Nernst equation)?
Permeability is a convenient measure; it takes into account all the ions contributing to membrane potential. So, Goldman is used when multiple different ions are contributing to membrane potential.
Which ionic species is the principle determinant of the membrane potential of a neuron in the resting state?
K+ is the principle determinant because of the relatively numerous K+ resting ion channels.
Which ionic species is the principle determinant of the membrane potential of a nerve cell at the peak of the action potential.
Na+ is predominant at the peak of the action potential because many voltage-gated Na+ channels have opened as a result of the action potential.
What is meant by "the conductance of a cell membrane to a particular ion"?
The summed conductance of all the passive channels for that ion.
What is "electromotive force"?
a source of electrical potential
What is a battery?
An electromotive force generated by a difference in chemical potentials
Compare permeability and conductance as measures of the ability of ions to cross membranes.
Permeability is an intrinsic property of the membrane and is a measure of the ease with which the ion passes through the membrane.
Conductance measure the ability of the membrane/channel to carry electrical current.
What is capacitance?
Capacitance is the passive property of the insulator that permits storage of charge when opposite surface of the nonconductor are maintained at a difference of potential.
What is the equation that relates voltage and capacitance?
V = Q/C
What are the 3 passive electrical properties of neurons that are important to electrical signaling?
1) Resting membrane potential
2) Membrane capacitance
3) Intracellular axial resistance along axons and dendrites
How do the passive electrical properties of neurons affect synaptic and/or action potentials?
They determine the time course and amplitude of the synaptic potential change generated by the synaptic current. They also determine whether a synaptic potential generated in a dendrite will result in a suprathreshold depolarization at the trigger zone on the axon hillock. Lastly, they influence the speed at which an action potential is conducted.
How does injection of negative or positive charges into neurons affect membrane potential?
Injecting a negative charge increases the charge separation across the membrane, making the membrane potential more negative (hyperpolarized). This relationship is linear: the larger the negative current, the greater the hyperpolarization.
Injecting a positive charge produces depolarization. The neuron behaves like a simple resistor, but only over a limited voltage range. A large enough positive current will produce a depolarization that exceeds threshold, at which point the neuron generates an action potential.
How does a small radius influence a cell's input resistance?
The radius is related to calculating the surface area of the cell. The smaller a cell's surface area, the fewer resting ion channels it possesses. Decreasing the number of resting ion channels decreases the conductance of the membrane, or in other words, increases the cell's input resistance. So, for a spherical cell, the input resistance would be inversely proportional to the square of the radius.
What are the physical properties of a capacitor that influence the amount of charge it can store?
1) surface area of the plates
2) insulation medium
3) distance between the plates
What is the effect on the membrane potentials of a small diameter neuron and a large diameter neuron when the same amount of current is injected into each cell?
Because capacitance (ability to hold charge) increases with the size of the cell, more charge, and therefore more current, is required to produce the same change in membrane potential in a larger neuron as in a smaller one.
What is the difference between resistive/ionic membrane current and capacitative membrane current?
Resistive/ionic membrane current is the physical movement of ions across the membrane.
Capacitative membrane current is the displacement of one charge from one plate by the addition of a like charge to the other plate; ions do not actually cross the membrane, but a current is still produced.
Define the membrane time constant.
The time it takes for the membrane to reach 63% of the final voltage after a change to the resting membrane potential.
What is the effect of neurite diameter on the resistance to current flow through the cytoplasm?
greater diameter means less axial resistance
What is meant by the term "length constant"?
It is the distance at which the voltage change has decayed 37% of its initial value at the point of current injection.
Compare Ra and Rm in a large and a small diameter neurite.
Both of these measurres decreases as diameter increases. However, Ra decreases more (because a is squared in the denominator). The length constant is related to Rm and Ra. A decreased Rm decreases the length constant, but a decreased Ra increases the length constant more than the Rm decreases it. As a result, thicker neurites have greater length constants and are able to transmit signals farther.
Is Ra or Rm more strongly influenced by neurite radius?
Ra
What is electrotonic conduction?
The passive spread of voltage changes along a neuron.
What are the two aspects of neuronal signaling that depend on electrotonic conduction?
Spatial summation relies on electrotonic conduction to convey numerous incoming signals to the trigger zone to set off the action potential.
Propagation of the action potential depends on electrotonic conduction to spread the depolarization down the neuron.
In a nerve with a mixed population of axons (small, medium, and large diameters), which population will be stimulated to fire action potentials first when a small amount of current is injected?
The large diameter neurons will fire at the lowest currents because the current can enter the large axons most easily and they are more difficult to bypass. The larger neurons have lower Ra values and can conduct current more easily.
What two factors determine the rate at which depolarization spreads along the axon?
Axial resistance
Membrane capacitance
What two strategies have evolved to increase the rate of action potential propagation in axons?
Increasing the diameter of the axon core decreases axial resistance. The inherent increase in surface area increases membrane capacitance, but overall the conductance is increased.
Myelination decreases capacitance and is more effective at increasing conduction velocity than diameter changes.
What is the function of the the nodes of Ranvier?
They prevent the action potential from dying out along the length of the myelinated axon. They are local regions of increased capacitance that boost the amplitude of the passing action potential.
What is the difference in the nodal membrane that increases the likelihood that an action potential will be triggered here?
The nodal membrane contains a high concentration of voltage-gated Na+ channels.
What is saltatory conduction?
At the nodes, the action potential slows and appears to "jump" quickly to the next node. This results in the fast/slow nature of conduction along a myelinated axon.
How do demyelinating diseases impair action potential propagation?
When the action potential reaches a demyelinated stretch, it transitions to a region of relatively greater capacitance and lesser membrane resistance that allows the action potential to die out relatively quickly. At best, it slows the action potential down.
When a neuron is subjected to a small, sustained depolarization of 10 mV and then allowed to repolarize, what current flow is observed?
There is a brief initial outward capacitive current, followed by a sustained outward ionic current that maintains the membrane at the 10 mV depolarization. At the end of the pulse there is a brief inward capacitative current, which brings the membrane back to the resting membrane potential.
What is the current flow like when a neuron is depolarized to zero?
There is an initial large-amplitude outward Ic (a current without literal ion movement across the membrane). then there is an outward Il (the current that flows through the resting ion channels). Shortly after the Il begins, an inward current develops, peaks, declines and gives way to an outward current, which reaches a plateau that is maintained for the duration of the pulse.
What function of a resting cell is served by the K+ channels through which the leakage current passes?
generation of the resting membrane potential
What does tetrodotoxin (TTX) do?
It binds and blocks voltage-gated Na+ channels with high affinity.
What does tetraethylammonium (TEA) do?
It blocks voltage-gated K+ channels with low affinity.
Hodgkin and Huxley subjected squid axon to large depolarizations in the presence of TTX or TEA. What were the results and their conclusions regarding the ionic current underlying the phases of the action potential?
They determined each ion's contribution by blocking the other ions' contributions with toxins. They determined that the Na+ open more rapidly than K+ channels and cause the inward current. Then the Na+ channels close, causing the peak of the inward current. The K+ channels which have opened allow the outward current to take over.
What is the effect of cocaine on Na+ channels?
Cocaine blocks voltage-gated Na+ channels like TTX does, but with less affinity.
Compare and contrast the responses of Na+ and K+ channels in excitable cells to a large depolarization.
Na+ channels open more quickly than K+ channels, but they also inactivate during sustained depolarization. K+ channels remain open for the duration of the depolarization.
What are the three states that Na+ channels can assume? How does each relate to membrane voltage?
1) Closed state: related to low Na+ conductance of the resting membrane potential
2) Depolarization: quickly transitions the channels to an activated state and allows influx of Na+
3) Sustained depolarization: slowly transitions the channels to the inactivated state which diminishes Na+ conductance and stops the inward current
What is the sequence of events during an action potential (as hypothesized by Hodgkin and Huxley)?
1) Depolarization opens Na+ channels, increasing Na+ conductance.
2) Depolarization also open K+ channels, but later than Na+ channels.
3)The potential is driven toward Na+'s resting potential but after a delay, Na+ channels are inactivated.
4) K+ channels remain open and repolarize, then hyperpolarize the cell.
What is the basis for the after-hyperpolarization phase of the action potential?
The K+ channels, which generate a current to repolarize the cell, are slow the close and result in an overshoot situation where the membrane is hyperpolarized.
Define "absolute refractory period" and "relative refractory period" and describe the ion channel behavior underlying each state.
Absolute refractory period: immediately after repolarization; the cell cannot be excited no matter what voltage is applied because of the residual Na+ inactivation.
Relative refractory period: occurs after the absolute refractory period; a time where stronger stimuli are required to excite the membrane because of increased open-state K+ channels.
How long does an action potential last?
1-10 ms.
Why are action potentials described as "all or none" signals? What is meant by the threshold of an excitable cell?
Only stimuli that are stronger than the threshold of an excitable cell will trigger an action potential. All weaker depolarizing stimuli are compensated for by resting channels.
How do Ca2+ influxes during the action potential modulate various voltage-gated channels?
Ca2+ influx carries a positive charge into the cell, contributing to depolarization. Some K+ channels are activated by a combination of Ca2+ ions and depolarization (caused by Ca2+). Intracellular Ca2+ can also close some Ca2+ channels.
What, besides Ca2+, can act as a second messenger to voltage-gated ions channels?
cAMP
Why does the trigger zone of a neuron have the lowest threshold for action potential generation?
It contains a large density of voltage-gated Na+ channels and typically contains voltage-gated channels that are more sensitive to smaller deviations in membrane potential.
What is a synapse?
The point at which one neurons communicates with another.
How many synapses does the average neuron make?
1,000
How many synaptic contacts are made with the average neuron?
1,000-10,000
Cerebellum Purkinje has 100,000
What is meant by "plasticity of nerve cells"?
The strength of synaptic transmission can be enhanced or reduced based on cellular activity.
What were the contributions of Charles Sherrington and Otto Loewi to our understanding of neuronal communication?
Sherrington coined the term "synapse" and described is as the zone of contact where one neuron communicates with another.
Loewi showed that the communication was accomplished by chemical signals and not the presumed electrical signals.
Chemical vs. Electrical synapses:
distance between pre and post-synaptic neurons
Chemical: 20-40 nm
Electrical: 3.5 nm
Chemical vs. Electrical synapses:
Cytoplasmic continuity between cells
Electrical only
Chemical vs. Electrical synapses:
Structure
Chemical: presynaptic vesicles and postsynaptic receptors
Electrical: gap junctions
Chemical vs. Electrical synapses:
transmission method
Chemical: neurotransmitters
Electrical: ion current
Chemical vs. Electrical synapses:
Delay
Chemical: .3 ms minimum delay with an average of 1-5 ms
Electrical: virtually none
Chemical vs. Electrical synapses:
Direction
Chemical: unidirectional
Electrical: bidirectional
Why has transmission at electrical synapses been described as electrotonic?
It is similar to the electrotonic transmission of subthreshold signals along neuronal processes.
How do pH and Ca2+ affect gap junction channels?
Lowered pH or elevated Ca2+ cause gap-junction channels to close. This serves to decouple damaged cells from healthy cells.
What are three functions of electrical synaptic transmission between neurons?
1) it transmits signals very rapidly
2) it connects large groups of neurons in synchronous activity
3) it transmits metabolic signals between cells (such as cAMP and IP3)
What are two situations in which glial cells utilize gap junctions to communicate?
1) Astrocytes can transmit Ca2+ intracellularly after electrical stimulation of certain pathways.
2)Schwann cells have gap junctions that hold layers of myelin together and transmit metabolites across the layers
In Marie Charcot Tooth disease, what is the failure of gap junction signaling?
The connexin mutation causes a failure in gap junctions in Schwann cells to transmit metabolites to the myelin sheath portions of the cell and results in demyelination.
What is the sequence of events that occur during synaptic transmission at a chemical synapse?
1) As the action potential discharges at the presynaptic membrane, voltage-gated channels allow Ca2+ to enter the cell.
2) The increased Ca2+ causes synaptic vesicle to bind to the active zone and release neurotransmitter into the synaptic cleft.
3) The neurotransmitter diffuses to the postsynaptic membrane and binds to receptors which directly or indirectly cause ion channels to open.
How is chemical transmission different from electrical transmission in terms of amplification of the signal by the postsynaptic cell?
The presynaptic membrane can release thousands of molecules of neurotransmitter, which diffuse and activate many ion channels. This means that under the right conditions, a weak signal in a small presynaptic neuron can cause a strong signal in a large postsynaptic neuron.
What are the two special features of most neuronal signaling?
It is fast and precisely directed.
What determines whether the action of a neurotransmitter on a postsynaptic cell is excitatory or inhibitory?
Receptors
What are the two common biochemical features of receptors for neurotransmitters?
1) They are membrane spanning
2) They carry out an effector function within the target cell, typically influencing ion channels
What is the difference between an ionotropic receptor and a metabotropic receptor?
Ionotropic receptors possess an extracellular domain that forms the receptor for the neurotransmitter, and a membrane-spanning domain that forms an ion channel.
Metabotropic receptors are distinct from the ion channels they affect; they act by altering intracellular metabolic reactions.
What is an example of an ionotropic receptor?
Nicotinic ACh receptor
What is an example of a metabotropic receptor?
Norepinephrine or serotonin receptors in the cerebral cortex.
Describe the electrical response in a skeletal muscle cell when ACh is released from the motor neuron axon that innervates it.
ACh is released from the motor neuron and binds to the receptor. This causes the end-plate membrane to depolarize rapidly and with large amplitude. This depolarization rapidly activates Na+ receptors in the junctional folds and generates an action potential that propagates along the muscle fiber.
How is the electrical response of a motor neuron different from the response of a neuron in the CNS?
The amplitude of depolarization is much greater at the end-plate (70 mV) than at a normal CNS synapse (1mV). This means that the CNS impulses must summate, while the muscle end-plate is triggered by a single action potential.
How many neurons make synaptic contact with a skeletal muscle, as compared to the number that contact a CNS neuron?
One neuron makes synaptic contact with a skeletal muscle fiber, while 1000s of neurons make synaptic contact with a CNS neuron.
What ions pass through the ACh-gated ion channels in muscle cells to produce the end-plate potential?
Na+ and K+
What are the two processes by which ACh is removed from the synaptic cleft at the neuromuscular junction?
Enzymatic hydrolysis
Diffusion
What is the location of acetylcholinesterase at the neuromuscular junction?
It is anchored to the extracellular matrix proteins.
What type of ACh-gated channels are found at the neuromuscular junction?
Nicotinic
Why are nicotinic receptors called ionotropic?
They contain a membrane-spanning domain that forms an ion channel.
What two toxins bind to nicotinic channels and block the action of ACh?
Curare/Tubocurarine (poison arrows)
alpha-bungarotoxin (snake venom)
What type of ACh receptor is metabotropic?
Muscarinic receptors
What are the steps in the process of synaptic transmission at the neuromuscular junction?
1) As the action potential discharges at the presynaptic membrane, voltage-gated channels allow Ca2+ to enter the cell.
2) Increased Ca2+ causes synaptic vesicles to bind to the active zone and release ACh into the synaptic cleft.
3)The ACh diffuses to the end-plate of the muscle cell and two ACh molecules bind to the two nicotinic ACh receptors.
3) This binding causes the receptor to open and allow Na+, K+, and Ca2+ to flow across the membrane.
4) The net influx of Na+ creates a depolarizing wave that reaches the voltage-gated Na+ channels in the junctional folds to trigger an action potential that is conducted along the muscle fiber.
What are the four differences between synaptic transmission between central neurons and synaptic transmission at the neuromuscular junction that make the former process more complex?
1) Central neurons receive input from hundreds of neurons while muscles receive one motor neuron.
2) Central neurons receive excitatory and inhibitory input while muscles receive only excitatory input.
3) Central neurons utilize many neurotransmitters while muscles utilize ACh only.
4) Central neurons require 50-100 depolarization inputs to fire while muscles require one action potential to fire.
What are the two broad categories of glutamate receptors? What are their functions?
Ionotropic glutamate receptors directly gate ion channels.
Metabotropic glutamate receptors indirectly gate ion channels through the use of a G protein to activate phospholipase C; this enzyme generates two second messengers, DAG and IP3.
What are the three main types of ionotropic glutamate receptors?
AMPA
Kianate
NMDA
What makes NMDA glutamate receptors different from other ionotropic glutamate channels?
1) They conduct Ca2+, as well as Na+ and K+, with high conductance.
2) The opening of the channel requires glycine as an extracellular cofactor.
3) The opening of the channel depends on a chemical transmitter and membrane potential/voltage through the action of a Mg+ plug.
What types of compounds block each of the three types of ionotropic glutamate receptors?
AMPA and kianate channels are both blocked by CNQX.
NMDA channels are blocked by APV and PCP.
Does the NMDA receptor normally contribute to the late or early phase of an EPSP?
Late
What are the effects of phencyclidine and antipsychotic drugs on the NMDA receptor? How does this relate to schizophrenia?
Hallucinogenic drugs block the NMDA receptor and antipsychotic drugs enhance current flow through the NMDA receptors. This is the basis for the relationship between schizophrenic hallucinations and defective NMDA channels.
Describe the mechanism behind glutamate excitotoxicity.
Toxic concentrations of glutamate allow excessive inflow of Ca2+ through NMDA channels. The Ca2+ activates calcium-dependent proteases and phospholipases which generate free radicals that damage the cell.
What are three neuropathological conditions in which glutamate toxicity contributes to neuronal damage and death?
Stroke
Status epilepticus
Huntington's disease
What is the major inhibitory neurotransmitter of the brain?
GABA
Are GABAA and GABAB receptors ionotropic or metabotropic?
GABAA: ionotropic
GABAB: metabotropic
What happens when GABA binds to GABAA and GABAB receptors?
When GABA binds to GABAA, it allows Cl- to pass.
When GABA binds to GABAB, it activates K+ channels through a second messenger.
What are three types of drugs that target GABAA receptors and what are examples of each type? What do these drugs do?
Benzodiazepines: diazepam (valium), iorazepam (ativan), clonazepam (klonopin)
Barbiturates: phenobarbital, secobarbital
Alcohol: ethanol

Each of these acts to increase the opening of the channel and enhance inhibitory synaptic transmission.
Which neuronal types release glycine as an inhibitory neurotransmitter?
Interneurons that inhibit antagonistic muscles.
Describe the mechanism by which glycine binding to its receptor causes hyperpolarization.
Glycine receptors gate Cl- channels. The positive current corresponds to an influx of Cl- down its electrochemical gradient, causing a net increase in total negative charge on the inside of the membrane's capacitance, so the membrane hyperpolarizes and the cell reaches -70 mV.
Compare the effects of an EPSP and an IPSP on the likelihood of a neuron reaching threshold and firing an action potential.
EPSPs increase the likelihood of a neuron firing an action potential, while IPSPs decrease the likelihood.
What is the relationship between the time constant and temporal summation?
The larger the time constant, the greater the likelihood that two sequential EPSPs at a site will generate an action potential.
What is the relationship between the length constant and spatial summation?
The larger the length constant, the greater the likelihood that two EPSPs at different sites will generate an action potential.
What are the five types of synaptic contact?
Axosomatic
Axodendritic
Axo-axonic
Dendrodendritic
Somasomatic
What is the relationship between proximity of a synaptic contact to the trigger zone and its effectiveness?
The strength (and effectiveness) of an electrotonic signal decreases over distance, so synaptic contacts closer to the trigger zone will be more effective than more distant synaptic contacts with the same stimuli.
Are synapses on the cell body and on dendritic spines usually inhibitory or excitatory?
Cell body synapses are usually inhibitory.
Dendritic spine synapses are usually excitatory.
What are the two major functions of synaptic receptors?
Recognition of specific transmitters
Activation of effectors.
What are the two families of metabotropic receptors?
G protein-coupled receptors
Receptor tyrosine kinases
List 9 examples of neurotransmitter receptors that are G protein-coupled receptors.
alpha-adrenergic receptors
beta-adrenergic receptors
muscarinic ACh receptors
GABAB receptors
certain glutamate receptors
certain serotonin receptors
certain neuropeptide receptors
odorant receptors
rhodopsin
What are three types of chemical signals that activate receptor tyrosine kinases?
Hormones
Growth factors
Neuropeptides
What are the two categories of second messengers?
Nongaseous
Gaseous
What are the 3 main components of the G protein signaling pathway?
1) external signal
2) receptor, bound to a transducer (G protein) and a primary effector
3) second messenger, which binds to a secondary effector
What are two examples of gaseous second messengers? How does each originate?
NO: generated by nitric oxide synthetase
CO: generated by heme oxygenase
How does NO function as a chemical signal in a nonneuronal cell type?
Epithelial cells release NO, which causes relaxation in the smooth muscle cells locally and results in vasodilation.
What are three properties of gaseous second messengers that allow them to function in transcellular signaling?
1) They pass through membranes readily.
2) They affect nearby cells without acting through a surface receptor.
3) They are extremely short-lived.
What is the cytoplasmic messenger that is synthesized in response to NO or CO? What is its action?
cGMP; it activates a specific protein kinase.
Ionotropic vs. Metabotropic receptors:
Physiological action
I: Excite or inhibit only
M: modulatory synapse action
Ionotropic vs. Metabotropic receptors:
Speed of onset
I: Fast
M: Slow
Ionotropic vs. Metabotropic receptors:
Duration of action
I: Short
M: Long
Ionotropic vs. Metabotropic receptors:
Effect on ion channels
I: Increase channel opening
M: Increase or decrease channel opening
Ionotropic vs. Metabotropic receptors:
Influence on neuronal electrical behavior
I: Excites or inhibits likelihood of action potential
M: Resting potential, input resistance, length and time constants, threshold potential, action potential duration, repetitive firing characteristics.
How do metabotropic receptors modulate synaptic actions of neurons?
1) The modulate transmitter release through actions on channels in presynpatic terminals.
2) They modulate fast synaptic potentials through transmitter-gated channels.
3) They modulate electrical excitability and neuronal firing properties through modulation of resting and voltage-gated channels in the cell body.
Compare the actions of ACh on nicotinic and muscarinic receptors at synapses in autonomic ganglia.
Stimulation of the presynaptic nerve releases ACh, which produces a fast EPSP by binding to and activating ionotropic nicotinic ACh receptors. This is followed by a slow EPSP, generated when ACh binds to metabotropic muscarinic receptors. Muscarine produces a decrease in K+ current by closing the M-type K+ channel. This depolarizes the cell and keeps the membrane excitable, prolonging the action potential.
How can second messengers endow synaptic transmission with long-lasting consequences?
1) They can alter gene expression through activation of transcription factors.
2) They can stimulate protein synthesis in specific dendritic spines of postsynaptic neurons.
What is the clinical use of dihydropyridines?
They selectively block L-type channels and are used to treat hypertension.
Define "quanta".
Discrete packages of neurotransmitter released from a synaptic vesicle.
Define "quantal synaptic potential".
the postsynaptic potential produced by one quantum of neurotransmitter
Define "miniature end-plate potential".
spontaneous, small synaptic potentials at neuromuscular synapses
What is the relationship between a quantum of neurotransmitter, a synaptic vesicle, and a miniature end-plate potential?
One quantum of neurotransmitter is contained in a synaptic vesicle, and the release of one quantum generates a miniature end-plate potential.
How does the number of quanta typically released at the neuromuscular junction compare to the number of quanta typically released between two neurons in the CNS?
150 quanta are released at the neuromuscular junction at each action potential, but only 1-10 quanta are released at CNS synapses at each action potential. This causes a much greater postsynaptic potential at the neuromuscular junction than at the CNS synapse.
Define "tetanic stimulation".
high frequency stimulation of the presynaptic neuron.
Define "posttetanic potentiation".
the increased size of postsynaptic membrane potentials after tetanic stimulation.
What is the hypothetical mechanism of posttetanic potentiation?
It is thought to be caused by residual Ca2+, which stems from the transient saturation of the Ca2+ buffering systems. The rapid large influx overwhelms the buffering systems and makes the cell more sensitive to Ca2+ increases.
What is the effect of presynaptic inhibition at axoaxonic synapses on the magnitude of the Ca2+ current that enters the presynaptic neuron?
It decreases the Ca2+ inward current and thereby decreases the amount of neurotransmitter released.
What is the effect of presynaptic facilitation at axoaxonic synapses on the magnitude of the Ca2+ current that enters the presynaptic neuron?
It increases the Ca2+ influx and thus increases the amount of neurotransmitter released.
What is the hypothesized cycle of events in neurotransmitter vesicle fusion with the presynaptic membrane?
1) The vesicles are anchored to the cytoskeletal elements in the presynaptic terminal by synapsin. Synapsin releases the vesicle when Ca2+ enters the presynaptic membrane and causes phosphorylation of synapsin.
2) Once the vesicles are released from the cytoskeleton, they can dock and bind to the terminal membrane through the action of SNARE molecules.
3)Vesicular SNARE (v-SNARE) proteins bind to terminal membrane SNARE (t-SNARE) proteins and cause the membranes to fuse, generating a fusion pore.
4) The fusion pore releases the neurotransmitter contents into the synaptic cleft.
5) The vesicular membrane is removed from the terminal membrane and recycled within the nerve terminal.
How do tetanus and botulinum toxins cause death?
They disrupt the SNARE proteins and prevent neurotransmitter release. If the toxins prevent neurotransmitter release at critical synapses in respiratory motor neurons, they can inhibit breathing muscles and cause death through respiratory failure.
What is a neurotransmitter?
A substance released at a synapse by one neuron that affects a postsynaptic cell in a specific manner.
What are some caveats of making general statements about neurotransmitter?
Targets can be neurons or other effector organs like muscles or glands.
They only act on close cells, while hormones act distally.
They must have a mechanism for removal from the site of action.
What is an autoreceptor?
A receptor on a presynaptic cell sensitive to the neurotransmitter that cell releases. It functions to modulate synaptic transmission in progress.
What are the 9 classic low molecular weight neurotransmitters?
Biogenic amines: ACh, DA, NE, Epi, Serotonin, Histamine
Amino acids: GABA, Gly, Glu
How is ACh synthesized?
Choline acetyltransferase changes Acetyl-CoA and choline into ACh and CoA.
Where is ACh used in body?
Neuromuscular junctions
Autonomic preganglionic neurons
Parasympathetic postganglionic neurons
Neurons from the nucleus basalis
Where are dopaminergic neurons found? To where do they project?
Substantia nigra and the arcuate nucleus. Substantic nigra neurons project along the nigrostriatal, mesolimbic, and mesocortical tracts. Arcuate nucleus neurons project to the pituitary gland.
Where are noradrenergic neurons found? To where do they project?
Nucleus ceruleus of the brainstem. They project throughout the cortex, cerebellum, and spinal cord. Postganglionic sympathetics are also noradrenergic.
Where are adrenergic neurons found?
in the brain in small number
Which of the four major dopaminergic tracts are affected by schizophrenia?
Mesolimbic and mesocortical tracts
Which of the four major dopaminergic tracts are affected by Parkinson's disease?
Nigrostriatal tract
Where are serotonergic neurons found? To where do they project?
In and around the midline raphe nuclei. They project widely in the brain and spinal cord.
What is the suspected relationship between serotonergic pathways and disorders of mood?
Serotonin is implicated in depression.
What is the amino acid precursor for histamine? Where are histaminergic neurons found?
Histadine
Hypothalamus
What is the principle inhibitory neurotransmitter of the nervous system?
GABA
Where are GABAergic neurons found?
1) spinal cord inhibitory interneurons
2) basket cells (inhibitory interneurons) of the cerebellum and hippocampus
3) Purkinje cells of cerebellum
4) Granule cells of olfactory bulbs
5) Amacrine cells of the retina
Where are glycinergic neurons found?
inhibitory interneurons of the spinal cord
What is the principle inhibitory neurotransmitter in the spinal cord?
Glycine
What are the purinergic neurotransmitters?
ATP
Adenosine
What are two examples of neurons that utilize purinergic neurotransmitters?
1) Autonomic neurons to the vas deferens, bladder, muscle fibers of the heart
2) Nerve plexuses on smooth muscle in the gut
What is the relationship between purinergic transmission and pain?
ATP released by tissue damage excites naked endings of peripheral C-fiber sensory axons.
Classical small vs. Peptide neurotransmitters:
Synthetic enzyme location
C: cytosol
P: vesicles
Classical small vs. Peptide neurotransmitters:
Synthesis location
C: Terminus mainly
P: Cell body
Classical small vs. Peptide neurotransmitters:
Synthesis mode
C: synthesized in active form
P: released from inactive precursors
Classical small vs. Peptide neurotransmitters:
Synthesized at a defined synaptic contact close to target postsynaptic cell?
C: Yes
P: No
Classical small vs. Peptide neurotransmitter:
Relative rates and duration of release
C: Can be rapid and sustained
P: Slow and long duration
What is meant by "coexistence of neurotransmitters"?
Peptide neurotransmitters and classical small neurotransmitters can both exist and be secreted and work synergistically on the same target cell.
What are the typical combinations of small and peptide neurotransmitters in a neuronal cell?
ACh and VIP (vasoactive intestinal peptide)
ACh and CGRP (calcitonin gene-related peptide)
Glutamate and dynorphin
What is cotransmission?
The coexistence of neurotransmitters released from a neuron and the presence of receptors for both on the target cell
How is the effect of ACh on the postsynaptic cell terminated?
When ACh dissociates with the receptor, acetylcholinesterase rapidly cleaves it into acetyl and choline, thereby punctuating its action. The choline is then taken up by a high-affinity choline transporter in the presynaptic cholinergic neuron terminus.
Where are MAO and COMT found and what do they do?
Monoamine oxidase and Catechol-o-methyltransferase are both found in the neuron cytoplasm and they both act to degrade biogenic amines.
What are the two clinical uses of MAO inhibitors?
Treatment of hypertension and depression
What is the most common mechanism by which neurotransmitters are removed from synaptic clefts?
re-uptake
What are the effects of cocaine on neurotransmitters?
Cocaine blocks the reuptake of NE.
What are the effects of tricyclic antidepressants and fluoxetine hydrochloride (Prozac) on neurotransmitters?
They block the reuptake of serotonin.
What is myasthenia gravis?
A disorder of function at the neuromuscular synapse. The term means "severe weakness of muscle".
What are the two forms of myasthenia gravis?
Autoimmune form
Congential form
What is the prevalence of the two forms of myasthenia gravis?
The prevalence of the autoimmune form is 50-125/million or 25,000 in the US.
Fewer than 100 cases of the congenital form have been identified.
What is the basic cause of the autoimmune form of myasthenia gravis?
Antibodies are produced against the nicotinic ACh receptor in muscle.
What are the 4 special characteristics of myasthenia gravis?
1) It affects CN-innervated muscles as well as limb muscles.
2) Severity of symptoms varies during the day, from day to day, and over longer periods.
3) It shows no signs of denervation and no EMG evidence of denervation.
4) Symptoms are improved by drugs that inhibit acetylcholinesterase.
What is the change in muscle compound action potential in patients with myasthenia gravis?
There is a rapid decrease in amplitude of the muscle compound action potential.
What morphological changes in neuromuscular junctions are found in patients with myasthenia gravis?
Nicotinic ACh receptors are less dense and numerous at the motor end-plate
Post-juctional folds are smoothed out
The synaptic cleft is enlarged
How do the junctional changes that occur in myasthenia gravis decrease the efficacy of transmission across the junction?
The changes decrease the likelihood that ACh released from the presynpatic neuron will reach the receptors. The wider synaptic cleft and reduced junctional folds increase the likelihood that ACh will diffuse away, and reduced numbers of receptors decreases the likelihood that it will bind to a receptor.
How does the decreased efficacy of transmission across neuromuscular junctions in myasthenia gravis patients relate to changes in the magnitude of the end plate potential, the decrease in amplitude of the muscle compound action potential, and the skeletal muscle weakness?
The decreases efficacy of transmission means that more signals from the presynpatic neuron will fail to bind to a receptor and cause depolarization. Fewer ACh connections with receptors results in the decreased end-plate potentials and decreased compound action potential amplitude. The reduced end-plate potentials and amplitude of compound action potentials causes decreased action potential firing in muscle cells and therefore muscle weakness.
Why might viral or bacterial infections trigger the autoimmune response that gives rise to myasthenia gravis?
The foreign organism antigen may share epitopes with the ACh receptor, so that when the body generates antibodies against the invader, the antibodies may also recognize and bind the ACh receptor. The similarity between the receptor antigen and the foreign antigen is called "molecular mimicry".
What are the consequence of antibody interaction with ACh receptors that might explain the morphological changes at the neuromuscular junctions in myasthenia gravis?
Cross-linking of multiple receptors could flag the receptor for degradation, thus increasing the turnover rate and decreasing the number of active receptors. Another hypothesis is that the bound antibody interferes with the binding of ACh to the receptor. However, we know that the antibody does not occupy the receptor's ACh binding site.
What is the past and present life expectancy and mortality rate among patients with myasthenia gravis?
25 years ago, the mortality rate was 33% (from respiratory distress). Now, few patients die from the disease.
What is the rationale for using acetylcholinesterase inhibitors to diagnose or treat myasthenia gravis?
The disease is mainly a problem with the lack of response to ACh by muscle cells. Relief from ACh inhibitors is a sign that the problem is myasthenia gravis and not denervation or another neurological disorder. ACh inhibitors decrease the rate that ACh is degraded and improves the likelihood that the ACh will activate a receptor.
What 4 treatments - besides acetylcholinerase inhibitors - have been used to treat the autoimmune form of myasthenia gravis?
1) Immunosuppresive therapy (coticosteriods and azathioprine) suppress antibody therapy and reduce the cause of the disease.
2) Plasmapheresis: removes plasma and therefore the offending antibody, provides transient relief, but patients still produce antibody.
3) Theymectomy: removes production of the antibody.
4) IVIG: reduces the antibody titer through mechanisms that are unclear.
What abnormalities are found in patients with congenital myasthenia gravis?
1) Deficiency of acetylcholinesterase at the end-plate.
2) Abnormalities of presynpatic nerve terminals (impaired release of ACh).
3) Congenital lack of aceytlcholinesterase.
4) Impaired capacity of ACh receptors to interact with ACh.
5) Abnormally low numbers of ACh receptors.
What is the effect of botulinus toxin on transmission across the neuromuscular junction and what is the treatment of botulism?
The toxin impairs ACh release from the presynaptic terminus. It is treated with calcium gluconate or guanidine, which promote release of ACh.