Midterm 2 pt2

Question 1

Neurotransmitters
Neuromodulator
Neurohormone

Answer 1

Neurotransmitters = chemicals exocytosed by neurons. Generates a postsynaptic response that may or may not be a change in voltage.

Neuromodulator = could be neurotransmitters but does not have to be. Does not function as a ligand on ionotropic receptors. However, they can alter the excitability of the channel. For example, permeability or probability of opening the channel may be changed. Neuromodulators change the characteristics of the channel.

Neurohormone = released from neurons and distributed by blood. Affects any cell in the body as long as receptors are available.

Question 2

Neuromodulation of ionotropic receptors

Answer 2

• Ionotropic receptors could have multiple sites for neuromodulators. When neuromodulators bind, it could change the properties of the channel.
• Neuromodulators are often broken down slowly, so it can have long lasting effects on the ionotropic channel
• Ex: If GABA neurotransmitter is present and the ionotropic channel opens, a neuromodulator could bind at a specific site to perhaps increase the probability of opening the channel

Question 3

Neurotransmitters binding to G-protein coupled receptor (GPCR)

Answer 3

Receptor+ligand > activates GPCR > activates ion channel
* Fast process
* Localized/specific

Receptor+ligand > activates GPCR > activates enzyme, second messengers
* Slower process
* Additional signaling molecules is synthesized inside the cell and diffuse
* Signal amplification
* Signal diversification

Question 4

G-protein activation

Answer 4

1) Ligand bind to GPCR. G-protein has alpha, beta, and gamma subunits.

2) In the alpha-subunit, GDP is exchanged for GTP in the G-protein alpha-subunit.

3) GTP-alpha-subunit detaches from beta-gamma-subunits. G-protein is activated and can activate other proteins in the cell.

4) Alpha-subunit has intrinsic GTPase, hydrolyzing GTP to GDP which deactivates the G-protein. Alpha, beta, and gamma subunits reunite.

Question 5

Neuromodulation of GPCR

Answer 5

Ex: norepinephrine increases the heart rate through neuromodulation by increasing the depolarizing current
**Norepinephrine binds to GPCR > activates G-protein > activates adenylate cyclase which produces cAMP > cAMP activates protein kinases > kinases phosphorylate the HCN channel > phosphorylation acts as neuromodulators, enhancing the passage of Na+ by enhancing the HCN channel > heart rate increases
**Neuromodulators made HCN open faster, allowing the Na+ to flow inside the cell, increasing the frequency of depolarization

Ex: acetylcholine decreases the heart rate through neuromodulation by increasing the hyperpolarizing current
**Acetylcholine binds to GPCR > activates G-protein > the activation of G-protein acts as modulators, enhancing the passage of K+ by enhancing the delayed rectifier K+ channel > heart rate decreases
**Neuromodulators made the delayed rectifier channel open faster, allowing the K+ to flow inside the cell, increasing the hyperpolarizing current… this slows the heart rate because now to reach action potential, cell has to overcome the low hyperpolarization voltage

Question 6

Stimulatory G-protein vs. Inhibitory G-protein

Answer 6

GPCR can either stimulate or inhibit certain protein/enzyme. They could regulate eachother’s functions.

Question 7

Homeostatic Synaptic Plasticity

Answer 7

Synaptic strength is regulated so that activity in the postsynaptic neuron remains relatively stable, even as the amount of synaptic activity changes

Auto-receptors of the presynaptic element (autonomic cell communication where the receptor is activated by neurotransmitters that the presynaptic neuron secretes) provide homeostatic plasticity through negative feedback

• Ex: Auto receptors and Cannabinoid receptors

Question 8

Activity Dependent Synaptic Plasticity

Answer 8

Strength of synapse is depend on previous history of activity at the synapse

• Gill withdrawl reflex
• Hippocampal long-term potentiation (LTP)
• Hippocampal long-term depression (LTD)
• Metaplasticity

Question 9

Gill withdrawl reflex

Answer 9

• Aplysia Californica is a type of sea slug
• The organ siphon is used for respiration. It pumps water out of the mantle and across the gill
• Gill withdrawl reflex is defense mechanism. When the animal is disturbed, the gill retracts to avoid injury

Question 10

Sensitizing gill withdrawl reflex
Explain the mechanism behind this process

Answer 10

• Reflex can be sensitized (exaggerated) by noxious stimulation (very strong painful stimuli such as electrical excitation)
• Reflex “learns” to retract the siphon more forcefully after the application of the noxious stimulus (this lasts for several minutes)
• Mechanism involves GPCR mediated presynaptic facilitation: noxious stimulation of the tail excites a serotonergic neuron (L29) that synapses onto the axon terminal of the siphon’s sensory neuron > serotonin activates a GPCR that activates a signaling cascade that leads to the inhibition of voltage gated K+ channels > inhibiting the voltage gated K+ channel prolongs the repolarization phase of the action potential > elongating the action potential increases neurotransmitter release from the siphon’s sensory neuron and therefore increases contraction of the gill

Question 11

If sensitization process is repeated…

Answer 11

• New synapse can grow to cause long lasting affects.
• Changes in synaptic plasticity are related to the modification of existing proteins. Long-term changes relate to protein synthesis.
• In the soma, new gene expression > new protein synthesized > stimulation of synapse growth > much stronger synapse connection

Question 12

Hippocampal pyramidal neurons: exhibit synapse-specific long-term potentiation (LTP) and long-term depression (LTD)

Answer 12

Synaptic Strength = amount of current or voltage excursion produced in the postsynaptic neuron by an action potential in the presynaptic neuron

• These are not permanent changes

LTP = synapse gets stronger = persistent strengthening of synaptic connections induced by a brief period of high-frequency presynaptic activity

LTD = synapse gets weaker = persistent weakening of synaptic connections induced by a brief period of low-frequency presynaptic activity

• LTP and LTD only applies to ACTIVE synapse (active/stimulated presynaptic neuron) and inactive neurons nearby are not affected

Question 13

Mechanism behind hippocampal LTP and LTD

Answer 13

• Hippocampal LTP and LTD are related to glutamatergic signaling at AMPA and NMDA receptors
• Mechanism of LTP: presynaptic neuron is releasing a lot of glutamate in response to high voltage excitation… post synaptic neuron has high EPSP… glutamate will bind at AMPA and NMDA receptors… a lot of AMPA will open and NMDA receptors will not be blocked by Mg+ when postsynaptic membrane is depolarized… lots of current can flow through the receptors
  *** Opening of the NMDA receptor will allow Ca2+ to enter the postsynaptic neuron. This is significant because it activates kinases (adds phosphate group). Kinases will phosphorylate and enhance AMPA receptor, making ions more permeable. Kinases will also add more AMPA receptors onto the membrane. Overall, this makes the synapse stronger.
• Mechanism of LTD: presynaptic neuron is releasing glutamate in response to low voltage excitation… post synaptic neuron has low EPSP… glutamate will bind at AMPA and NMDA receptors… not a lot of AMPA will open due to low glutamate concentration and NMDA receptors will be blocked by Mg+ when postsynaptic membrane is at resting potential… not a lot of current can flow through the receptor
  *** Closed NMDA receptor will not allow Ca2+ to enter the postsynaptic neuron. Small Ca2+ concentration inside the post synaptic neuron would activate phosphatase (removes phosphate group). AMPA receptors become less efficient and even removed/internalized from the cell membrane. Overall, this makes the synapse weaker.

SUMMARY:::

• Long-term potentiation (LTP) = NMDA receptor signals simultaneous pre/postsynaptic depolarizations, large postsynaptic [Ca2+] activates protein kinases, AMPA phosphorylated and added to membrane
• Long-term depression (LTD) = NMDA receptor signals asynchronous pre/postsynaptic depolarizations, small postsynaptic [Ca2+] activates protein phosphatases, AMPA dephosphorylated and internalized

Question 14

NMDA receptor currents are required for learning
* Radial Arm Maze
* Morris Water Maze

Answer 14

• Radial Arm Maze: food was placed around the maze. First trial, the mouse scavenged around the maze for food. On the second trial, the mouse learned and remembered the placement of the food and efficiently traveled to find the food around the maze. > Without NMDA receptors, this learning process did not occur. The first trial was same as second trial
• Morris Water Maze: hidden platform was placed within a pool of water. First trial, the mouse scavenged around the water for a platform. On the second trial, the mouse learned and remembered the placement of the platform and efficiently traveled to find the platform around the water. > Without NMDA receptors, this learning process did not occur. The first trial was same as the second trial

Question 15

Check and Balances prevent hyperactivity

Answer 15

• Auto-receptors = GCPR on the presynaptic neuron, inhibits neurotransmitter release
• Endocannabinoids = released from the postsynaptic neuron, bind presynaptic GPCR, inhibit neurotransmitter release
• Metaplasticity = LTP changes not only AMPA receptors, but also NMDA receptors (negative feedback loop)

Question 16

Metaplasticity

Answer 16

• Previous history of LTP lowers the liklihood of further LTP by affecting the physiology of the NMDA receptor
• NMDA receptor is comprised of 4 subunits: two NR1 subunits, and two NR2 subunits
• NR2B subunits are associated with greater Ca2+ permeability. NR2A subunits are associated with less Ca2+ permeability.
• LTP increases NR2A levels, making additional LTP more difficult.
• However, LTD decreases NR2A levels, making LTP possible in the future.

Question 17

Synaptic Remodeling

Answer 17

• Synaptic remodeling relates to long lasting changes in the strength of signaling between neurons
• The initial induction of LTP lasts hours
• Maintenance of this over longer periods of time (weeks/months/years) relates to protein synthesis
• Synaptic remodeling requires gene expression (this process takes a long time)
• Gene expression is regulated by transcription factors and the CREB transcription factors are important for memory.
• Phosphorylated CREB-1 promotes transcription
• CREB-2 inhibits transcription

Ca2+ > activate protein kinases > CREB-1 is phosphorylated > result in protein synthesis

Question 18

The expression of CREB-1 and CREB-2 affect the fruit fly’s ability to learn avoidance behaviors related to odor shock pairings

Answer 18

• Overexpression of CREB-2 (inhibits transcription) blocks memory consolidation
• Overexpression of CREB-1 (promotes transcription) improves memory consolidation

Question 19

Synaptic Pruning

Answer 19

• The process in which the brain removes neurons and synapses that it does not need
• We are born with more neural connections than we really need. This insures that all necessary neurons are active and functional. In the future, when the synapse are regarded as unimportant, then it is removed.

Question 20

Neuronal Polarization

Answer 20

After the neurons have formed and migrated to its correct location, it can begin to grow its neurites.

Polarization (the differentiation of neurites into axon or dendrites) is related to extracellular morphogen chemicals and cell surface receptors

Morphogen binding to specific receptors will initiate the growth of either axon or dendrite, growing in appropriate directions.

Question 21

Axon Guidance

Answer 21

Extracellular chemicals and cell surface receptors promote dynamic regulation of the cytoskeleton, leading to directional neurite growth.

*** Growth cones are formed at the tips of developing axons and dendrites. These are highly motile structures that explore the extracellular environment, determine the direction of growth, and then guide the extension of the axon in that direction.

Cytoskeletons include microtubules, neurofilaments, and microfilaments:
* Axons are guided to their target by a growth cone and receptors on the growth cone detect chemicals in the extracellular environment.
* At the edges of the growth cone, filopodia extend into the environment via actin polymerization. Environmental cues promote or inhibit actin polymerization.
* A chemo-attractant (small molecules in the external cell environment) promotes actin polymerization and a chemo-repellant inhibits actin polymerization.
* Microtubules grow into the leading edge of the growth cone, resulting in directional growth

Question 22

Example of how extracellular chemicals can direct growth path of neuron in CNS

Answer 22

• Decussation (crossing the midline) by neuron in the CNS is driven by chemicals Netrin and Slit as well as receptors DCC (netrin receptors) and Rob (slit receptors)
• Netrin and Slit are secreted at the ventral midline of the CNS
• Netrin = chemo attractant
• Slit = chemo repelant
• Initially, the growth cone displays Netrin receptors (DCC) and grows toward the area of highest Netrin concentration. After reaching the midline, the growth cone displays Slit receptors (Robo) and grows away from the area of highest Slit concentration.
• At the end, the neuron moved from left to right side of the CNS

Question 23

Fasciculation

Answer 23

• Fasciculation can create common growth paths when growth cones navigate via contact interactions.
• Process that can allow multiple axons to navigate together via cell adhesion molecules.
• Cell adhesion molecules on the cell membrane allows cells to adhere to each other.

Question 24

Synaptogenesis

Answer 24

Series of interactions between the developing dendrite and the developing axon. This interaction will result in exchange of signals and forming a synapse. Pre synaptic cell will begin to form synaptic vesicles. Post synaptic cell will begin to create receptor clusters

• Growing dendrites constantly reach out through filopodium. This could interact with the growing axon, resulting in synaptogenesis.

Question 25

Example of synaptogenesis: specific to the neuromuscular junction

Answer 25

• At the NMJ, development of the postsynaptic density is promoted by the release of presynaptic Agrin molecules
• Agrin molecules bind with Agrin receptor > activate Rapsin protein which calls for ACh receptors to cluster on the cell membrane > result in maturation of synapse

Question 26

Activity Dependent Pruning: development of many more neurons than necessary

Answer 26

• Developing circuits create many more neurons than are present at maturity. Competition for trophic factors inhibits apoptosis.
• Mechanism: postsynaptic neuron secretes trophic factors (survival factors) that bind to trophic receptors on the presynaptic neuron. If this binding occurs, apoptosis of presynaptic neuron is inhibited.

Question 27

Activity Dependent Pruning: development of many more synapses than necessary

Answer 27

• Developing circuits create many more synapses than are present at maturity. Activity plays an important role in pruning.
• Synapses that will persist will be those that fire the postsynaptic cell
• Mechanism: during pruning, the weakest synapses are eliminated (pruning will not occur if differences in strength of synapse cannot be determined). Pruning at the NMJ is arrested by global antagonists. Pruning at the NMJ is accelerated by local antagonists.

Question 28

Activity Dependent Pruning: developing visual system

Answer 28

• In the developing visual system, neural activity plays an important role in refining the pattern of neural connections to produce segregation.
• Target neurons contacted by numerous axons from the same retina will fire in synch with inputs from that retina and the connections will be strengthened and retained.
• Over time, the pathway becomes segregated with postsynaptic targets responding only by inputs from the left retina, or only by inputs from the right.
• Neurons from each eye has coordinated activity.
• “Neurons that fire together wire together” and “Neurons that fire out of sync loose their link”

Question 29

Pruning requires synchronous firing of the presynaptic and postsynaptic neuron… how are inhibitory synapse wired?

Answer 29

• Inhibitory synapses can be excitatory during development. This is due to the different in ion concentration gradient during development, compared to maturity.
• Immature neurons are excited by GABA and can wire according to principles of Hebbian plasticity (neurons that fire together wire together).
• Mature neurons express the K/Cl cotransporter (KCC2) which uses the outward K+ current to drive Cl- out of the cell.
• Immature neurons express the Na/K/Cl cotransporter (NKCC1) which uses the inward Na+ current to drive Cl- into the cell.
• The Cl- equilibrium potential is negative in a mature neuron… but positive in an immature neuron.