Chapter 7 The Nervous System Checkpoint

Give examples of endogenous opioid polypeptides, and discuss their significance.

-A burst in beta-endorphin secretion was shown to occur in pregnant women during childbirth; when activated by stressors it can block the transmission of pain.

Describe the sequence of events by which action potentials stimulate the release of neurotransmitters from presynaptic axons.

1) Action potential conducted by axon reaches axon terminal 2) Voltage-gated Ca2+ channels open 3) Ca2+ binds to sensor protein in cytoplasm 4) Ca2+-protein complex stimulates fusion and exocytosis of neurotransmitter

Compare the properties of EPSPs and action potentials and state where these events occur in a postsynaptic neuron.

Action potentials occur in the axons where voltage-regulated channels are located, whereas EPSPs occur in the dendrites and cell body. Action potentials have a threshold, EPSPs have no threshold, because the ACh released from a single synaptic vesicle produces a tiny depolarization of the postsynaptic membrane. When more vesicles are stimulated to release ACh, the depolarization is correspondingly greater (meaning it is graded in magnitude). This is not the case with all-or-none action potentials. Since EPSPs can be graded and have no refractory period, they are capable of summation. Action potentials are incapable of summating due to their all-or-none nature and refractory periods.

Describe the structure of the sheath of Schwann, or neurilemma, and explain how it promotes nerve regeneration. Explain how a myelin sheath is formed in the PNS.

All axons in the PNS are surrounded by a continuous living sheath of Schwann cells, known as the neurilemma or, sheath of Schwann. After injury, Schwann cells in the PNS form a regeneration tube, which is believed to secrete chemicals that attract the growing axon tip, and the tube helps guide the regenerating axon to its proper destination. In the PNS, these inhibitory proteins are also produced, but then the Schwann cells stop producing them, allowing for axon regeneration. A Schwann cell wraps around the axon, forming several layers, squeezing the cytoplasm to the outside. The outer part is known as the neurilemma, or sheath of Schwann. The many layers of myelin underneath the neurilemma is the myelin sheath. This provides insulation around the axon, exposing the nodes of Ranvier.

Explain the all-or-none law of action potentials, and describe the effect of increased stimulus strength on action potential production. How do the refractory periods affect the frequency of action potential production?

All-or-none law- Depolarization has to reach a certain threshold or the voltage-regulated gates remain closed. When it reaches that threshold the gates open, and this produces a maximum potential change. Since the channels are only open for a fixed period of time and are soon inactivated (lasting until the membrane has repolarized) all action potentials have about the same duration. Since the concentration gradient for Na+ is relatively constant, the amplitudes of the action potentials are about equal in all axons at all times (from -70mV to +30mV, or about 100 mV in total amplitude). As stimulus strength is increased, the frequency of action potentials will increase accordingly. As the action potentials are produced with increasing frequency, the time between successive action potentials will decrease- but only up to a minimum time interval. The interval between successive action potentials will never become so short as to allow a new action potential to be produced before the preceeding one has finished. This is because when a voltage-regulated channel is opened for depolarization for a set time, it enters an inactve state, and can't be opened by depolarization.

Explain what is meant by the blood-brain barrier. Describe its structure and discuss its clinical significance.

Capillaries in the brain do not have pores between adjacent endothelial cells (they are joined by tight junctions). This means that molecules can only pass through by diffusion, active transport and exocytosis and endocytosis. This is a very selective process, only certain nonpolar molecules (ex. O2) and organic molecules (ex. alcohol) can pass through the plasma membranes of capillaries. Everything else requires ion channels and carrier proteins. The blood-brain barrier presents difficulties in the chemotherapy of brain diseases because drugs that could enter other organs may not be able to enter the brain. In the treatment of Parkinson's disease, patients who need a chemical called dopamine in the brain are often given an a precursor molecule called levodopa (L-dopa) because L-dopa can cross the blood-brain barrier but dopamine cannot. Some antibiotics also cannot cross the blood-brain barrier; therefore in treating infections such as meningitis, only those antibiotics that can cross the blood-brain barrier are used.

Explain how cocaine and amphetamines produce their effects in the brain. What are the dangers of these drugs?

Cocaine binds to the reuptake transporters for dopamine, norepinephrine and seratonin and blocks their reuptake into the presynaptic axon endings. This results in overstimulation of those neural pathways that use dopamine as a neurotransmitter, producing feelings of euphoria. It causes social withdrawal, depression, dependence upon even higher doses, and serious cardiovascular and renal disease, which can cause heart disease and kidney failure.

Describe the structure, locations, and functions of gap junctions.

Depolarization flows from presynaptic cell into postsynaptic cell through channels called gap junctions. -The membranes of the two cells are separated by only 2 nanometers. A surface view of gap junctions in the electron microscope reveals hexagonal arrays of particles that function as channels through which ions and molecules may pass from one cell to the next. Composed of 12 proteins (connexins), which are arranged like staves of a barrel to form a water-filled pore. -Present in cardiac muscle, where they allow action potentials to spread from cell to cell, so that the myocardium can contract as a unit. In smooth muscles, they allow many cells to be stimulated and contract together, producing a stronger contraction (i.e. the uterus during labor). -Found between neurons in the brain, where they can synchronize the firing groups of neurons. -Also found between neuroglial cells, where they are believed to allow the passage of Ca2+ and other ions and molecules between the connected cells. -Function: neurotransmitters and other stimuli, acting through second messengers such as cAMP or Ca2+, can lead to phosphorylation or dephosphorylation of gap junctions connexin proteins, cause the opening or closing of gap junction channels.

Define the terms depolarization and repolarization, and illustrate these processes graphically.

Depolarization: A change in the cell, in which positive charges flow into the cell, due to appropriate stimulation. Repolarization: A return to the resting membrane potential.

Describe the relationship between dopaminergic neurons, Parkinson's disease, and schizophrenia.

Drugs used to treat schizophrenia act against the D2 subtype of dopaminergic receptor, which can cause side effects resembling Parkinson's disease. This suggests that overactivity of the mesolimbic dopamine pathways contributes to schizophrenia, which also helps explain why people suffering from Parkinson's disease could develop schizophrenia if they are treated with too much L-dopa (which increases dopaminergic transmission).

List the monoamines and indicate their chemical relationships.

Epinephrine, norepinephrine, dopamine and seratonin. Seratonin is derived from the amino acid tryptophan. Epinephrine, norepinephrine and dopamine are derived from the amino acid tyrosine and form a subfamily of monoamines called catecholamines. Epinephrine (AKA adrenaline) is a hormone secreted by the adrenal gland, not a major neurotransmitter, while norepinephrine functions as both a hormone and a neurotransmitter (a neurohormone).

Describe how action potentials are conducted by unmyelinated nerve fibers. Why is saltatory conduction in myelinated fibers more rapid?

Every patch of membrane that contains Na+ and K+ channels can produce an action potential. The spread of depolarization by the cable properties of an axon is fast compared to the time it takes to produce an action potential. So the more action potentials along a given stretch of axon that have to be produced, the slower the conduction. Since action potentials must be produced at every fraction of a micrometer in an unmyelinated axon, the conduction rate is relatively slow. In a myelinated axon, there are basically only Na+ channels concentrated in the nodes of Ranvier. Action potentials only occur at the nodes and metaphorically "leap" from node to node (saltatory conduction). Myelinated axons conduct impulses faster because the voltage-gated channels are only at the nodes, and they have more cablelike spread of depolarization (which is faster) and fewer sites where action potentials are produced (which is slower) than unmyelinated axons.

Describe the mechanism of action of glycine and GABA as neurotransmitters, and discuss their significance.

GABA and glycine hyperpolarize the postsynaptic membrane, producing an IPSP. The binding of glycine and GABA to its receptor proteins causes chloride channels (Cl-) to open in the postsynaptic membrane, causing Cl- to diffuse in, making the the membrane potential even more negative than it is at rest, and therefore farther from the threshold depolarization required to stimulate action potentials. With glycine, this is important in motor control, because when flexor muscles are stimulated, the antagonistic muscles are inhibited, and vice versa. With GABA, purkinje cells mediate the motor functions of the cerebellum by producing IPSPs in their postsynaptic neurons.

Explain the significance of glutamate in the brain and of NMDA receptors.

Glutamate: They function as the major excitatory as neurotransmitters in the CNS. They produce EPSPs and research has revealed that each of the the glutamate receptors encloses an ion channel, similar to the nicotinic ACh receptors. There are 3 subtypes of glutamate receptors, named after the molecules (other than glutamate) that they bind: 1) NMDA receptors 2) AMPA receptors 3) kainate receptors NMDA: The ion channel will not open, simply by the binding of glutamate to its receptor. Two other conditions must be met at the same time: 1) NMDA receptor must also bind to glycine 2) The membrane must be partially depolarized at this time by a different neurotransmitter molecule that binds to a different receptor. Once open, the NMDA receptor channels permit the entry of Ca2+ and Na+ (and exit of K+) into the dendrites of the postsynaptic axon.

Explain how postsynaptic inhibition is produced and how IPSPs and EPSPs can interact.

In the brain it is produced by GABA, in the spinal cord it is produced by glycine. EPSPs and IPSPs to a postsynaptic neuron, can summate in an algebraic fashion. The effects of IPSPs reduce or eliminate the ability of EPSPs to generate action potentials in the postsynaptic cell.

Describe the function of acetylcholinesterase and discuss its physiological significance.

It is an enzyme present on the post-synaptic membrane, or immediately outside the membrane with its active site facing the synaptic cleft. AChE hydrolyzes ACh into acetate and choline, inactivating ACh, and stopping the activity in the postsynaptic cell. Acetate and choline can reenter the presynaptic axon terminals and then be resynthesized into ACh.

Distinguish between the two types of chemically regulated channels and explain how ACh opens each type.

Ligand-gated channels: Two of the five polypeptide units of nicotinic ACh receptors conatin ACh binding sites, and the channel opens when both sites bind to ACh. The opening of this channel permits the simultaneous diffusion of Na+ and K+ out of the postsynaptic cell. The flow of Na+ predominates because of the steeper electrochemical gradient. This produces the depolarization of an EPSP. G-protein-coupled channels: These are opened by the binding of a neurotransmitter to its receptor protein, but the receptor and ion channel are different, separate membrane proteins. So the binding of the neurotransmitter opens the channel indirectly. The muscarinic ACh receptors are formed from a single subunit, and binds to one ACh molecule. When ACh binds to the receptor it activates G-proteins in the cell membrane (composed of alpha, beta and gamma subunits). Alpha subunit dissociates from the other two subunits (which stick together and form a beta-gamma complex). Depending on the specific case, either the alpha of the beta-gamma complex then diffuses down the membrane until it binds to an ion channel, causing it to open or close. This indirectly affects the permeability of K+ channels, causing either a depolarization or hyperpolarization.

Describe how the permeability of the axon membrane to NA+ and K+ is regulated and how changes in permeability to these ions affect the membrane potential.

NA+ and K+ pass through ion channels in the plasma membrane that are said to be gated channels. The "gates" are part of the proteins that compose the channels, and can open or close the ion channels in response to a particular stimuli. When ion channels are closed, the plasma membrane is less permeable, and when the channels are open, the membrane is more permeable to an ion. There are two types of channels for K+. One types is gated, and the gates are closed at the resting membrane potential. The other types is not gated; these K+ channels are thus always open and are often called leakage channels. Channels for Na+ are all gated and the gates are closed at the resting membrane potential. However, the gates of closed Na+ channels appear to flicker open (and quickly close) occasionally, allowing some Na+ to leak into the resting cell. As a result of these ion channel characteristics, the neuron at the resting membrane potential is much more permeable to K+ than Na+, but some Na+ does enter the cell. Because of the slight inward movement of Na+, the resting membrane potential is a little less negative than the equilibrium potential for K+. Depolarization of a small region of an axon can be experimentally induced by a pair of stimulating electrodes that act as if they were injecting positive charges into the axon. By this sudden stimulation, a sudden and very rapid change in the membrane potential will be observed. This is because depolarization to a threshold level causes the Na+ channels to open. Now, for an instant, the plasma membrane is freely permeable to Na+. Because the inside of the cell is negatively charged relative to the outside, and the concentration of Na+ is lower inside the cell, the electrochemical gradient for Na+ causes Na+ to rush into the cell. This causes the membrane potential to move rapidly toward to Na+ equilibrium potential. The increased Na+ within that tiny region of an axon membrane greatly affects the membrane potential. A fraction of a second after the Na+ channels open, they close due to an inactivation process. Just before they do, the depolarization stimulus causes the gated K+ channels to open. This makes the membrane more permeable to K+ than it is at rest, and K+ diffuses down its electrochemical gradient out of the cell. This causes the membrane potential to move toward to K+ equilibrium potential. The K+ gates will then close and the permeability properties of the membrane will return to what they were at rest.

Draw a neuron, label its parts and describe the functions of these parts.

Neurons generally have 3 principle regions: (1) Cell body- the enlarged portion of the neuron that contains the nucleus. It is the "nutritional center" of the neuron where macromolecules are produced. (2) Dendrites- thin, branched processes that extend from the cytoplasm of the cell body; they are the receiving end of the neuron that transmits graded electrochemical impulses to the cell body. (3) Axon- the longer process that conducts information, called action potentials away from the cell body.

Describe the location of neurotransmitters within an axon and explain the relationship between presynaptic axon activity and the amount of neurotransmitters released.

Neurotransmitter molecules within the presynaptic neuron endings are contained within many small, membrane-enclosed synaptic vesicles. In orders for the neurotransmitter to be released into the synaptic cleft, the vesicle membrane must fuse with the axon membrane in the process of exocytosis. When there is a greater frequency of action potentials at the axon terminal, there is a greater entry of Ca2+, and thus a larger number of synaptic vesicles undergoing exocytosis and releasing neurotransmitter molecules. As a result, a greater frequency of action potentials by the presynaptic axon will result in greater stimulations of the postsynaptic neuron.

Explain how myelin sheaths are formed in the CNS. How does the presence or absence of myelin sheaths in the CNS determine the color of this tissue?

Oligodendrocytes have tentacles which branch to many axons, forming myelin sheaths around them. This is unlike a Schwann cell, which wraps around only one axon. This forms the white matter of the CNS. The myelin sheaths around axons of the CNS give this tissue a white color; areas of the CNS that contain a high concentration of axons thus form the white matter (myelinated). The gray matter of the CNS is composed of high concentrations of cell bodies and dendrites, which lack myelin sheaths.

Explain how nitric acid is produced in the body, and describe its functions.

Produced by nitric oxide synthetase in the cell of many organs from the amino acid L-arginine. -Acts as a local tissue regulator that causes the smooth muscles of those vessels to relax, so that the blood vessels dilate. -Within macrophages and other cells, nitric oxide helps to kill bacteria. -Nitric oxide is a neurotransmitter of certain neurons in both the PNS and CNS. It diffuses out the presynaptic axon and into neighboring cells by simply passing through the lipid portion of the cell membranes. -In some cases, also produced by the postsynaptic neuron and can diffuse back to the presynaptic neuron to act as a retrograde neurotransmitter. -Once in the target cells, NO exerts its effects by stimulating the productions of cyclic guanosine monophosphate (cGMP), which acts as a second messenger. -In the PNS, nitric oxide is released by some neurons that innervate the GI tract, penis, respiratory passages, and cerebral blood vessels. These are autonomic neurons that cause smooth muscle relaxation in their target organs.

Distinguish between sensory neurons, motor neurons, and association neurons in terms of structure, location, and function.

Sensory (afferent) neurons: Conducts afferent impulses to CNS. They are pseudounipolar (one of the branched processes receives sensory stimuli, and produces nerve impulses, the other delivers nerve impulses to synapses within the brain or spinal cord) Motor (efferent) neurons: Efferent, conducts impulses away from the CNS. They are multipolar, with several dendrites and one axon extending from its cell body. There are 2 types- somatic and autonomic. Somatic are responsible for reflex and voluntary control of skeletal muscles. Autonomic are responsible for innervation of smooth muscle, cardiac muscle and glands. Association neurons (interneurons): Bipolar, with a dendrite extending from a process on one side of cell body, and an axon extending from a process on the other side. These are responsible for the integrative functions of the nervous system and are only found in the CNS.

Define spatial summation and temporal summation, and explain their functional importance.

Spatial summation- Results from the convergence (a number of axons synapsing onto one) of presynaptic axon terminals on the dendrites and cell body of a postsynaptic neuron. Since synaptic potentials are graded and lack refractory periods (unlike action potentials) this allows them to summate as they are conducted by the postsynaptic neuron. Temporal summation- The successive activity of a presynaptic axon terminal causes successive waves of transmitter release, resulting in summation of EPSPs in the postsynaptic neuron. This summation helps to determine if the depolarization that reaches the axon hillock will be a sufficient magnitude to generate a new action potential.

State a location at which ACh has stimulatory effects. Where does it exert inhibitory effects? How are stimulation and inhibition accomplished?

Stimulatory- In the smooth muscle cells of the stomach the binding of ACh to its muscarinic receptors can cause a G-protein alpha subunit to dissociate, and bind to K+ channels. This causes the K+ channels to close and results in the outward diffusion of K+ to reduce below resting levels. The reduction of the outward flow of K+ produces a depolarization, producing an EPSP, resulting in contractions of the stomach. Inhibitory- In the heart muscle cells, the binding of the ACh to its muscarinic receptors can cause the G-protein beta-gamma subunits to dissociate and bind to gated K+ channels. This causes K+ channels to open, causing outward diffusion of K+ out of the cell. This results in hyperpolarization of the cell, producing an IPSP, slowing the heart rate.

Describe the mechanism of presynaptic inhibition.

The amount of an excitatory neurotransmitter released at the end of an axon is decreased by the effects of a second neuron, whose axon makes a synapse with the axon of the first neuron (axoaxonic synapse). The neurotransmitter exerting this presynaptic inhibition may be GABA, or excitatory neurotransmitters such as ACh and glutamate. Excitatory neurotransmitters can cause presynaptic inhibition by producing depolarization of the axon terminals, leading to inactivation of Ca2+ channels, decreasing the inflow of Ca2+ into the axon terminals and thus inhibiting the release of neurotransmitter.

Explain how EPSPs produce action potentials in the postsynaptic neuron.

The dendrites and cell body are the receptive area of the neuron, and where the receptor proteins for neurotransmitters are located. If enough neurotransmitter is received (since they summate) and the depolarization is at or above threshold when it reaches the initial segment of the neuron (right around the axon hillock) the EPSP will stimulate the production of an action potential. Gradations in the strength of the EPSP determines the frequency with which action potentials will be produced at the axon hillock, and the action potentials at this point serve as the depolarization stimuli for the next region, and so on.

Explain how monoamines are inactivated at the synapse and how this process can be clinically manipulated.

The stimulatory effects of the monoamines, like those of ACh, must be quickly inhibited as to maintain proper neural control. It is stopped by 1) reuptake of the neurotransmitter molecules from the synaptic cleft into the presynaptic axon terminal, then 2) degradation of the monoamine by an enzyme within the axon terminal called monoamine oxidase (MAO).

Distinguish between voltage-regulated and chemically regulated ion channels.

Voltage-regulated: found primarily in the axons; open in response to depolarization Chemically-regulated: found in the postsynaptic membrane; open is response to the binding of postsynaptic receptor proteins to their neurotransmitter ligand

Describe long-term potentiation, explain how it is produced, and discuss its significance.

When a presynaptic neuron is experimentally stimulated, the excitability is enhanced-or, potentiated- when this neuron pathway is subsequently stimulated. The improved efficacy of synaptic transmission may last hours, or even weeks. It is caused when the presynaptic neuron releases its neurotransmitter 5-15 milliseconds before the postsynaptic neuron fires its action potential. Both LTP and LTD require the diffusion of Ca2+ into the postsynaptic neuron, but with LTP the influx of Ca2+ is large and rapid compared to LTD.

Describe how gating of NA+ and K+ in the axon membrane results in the action of action potential.

When the axon membrane has been depolarized to a threshold level, by stimulating electrodes-- the NA+ gates open and the membrane becomes permeable to Na+. This permits Na+ to enter the axon by diffusion which further depolarizes the membrane ( make the inside less negative, or more positive). The gates for the Na+ channels of the axon membrane are voltage regulated, and so this additional depolarization opens more NA+ channels and makes the membrane even more permeable to Na+. As a result, more Na+ can enter the call and induce a depolarization that opens even more voltage-regulated Na+ gates. A positive-feedback loop is thus created, causing the rate of Na+ entry and depolarization to accelerate in an explosive fashion. The explosive increase in Na+ permeability results in a rapid reversal of the membrane potential in that region from -70 mV to +30 mV. At that point the channels for Na+ close (become inactivated) causing a rapid decrease of Na+ permeability. As a result of a time-delayed effect of the depolarization, voltage-gate K+ channels open and K+ diffuses rapidly out of the cell. Because K+ is positively charged, the diffusion of K+ out of the cell is less positive, or more negative, and acts to restore the original resting membrane potential of -70 mV (repolarization and represents a negative feedback loop). These changes in NA+ and K+ diffusion and the resulting changes in the membrane potential they produce constitute an action potential, or nerve impulse.