Lecture 8- Neuroplasticity

You are examining long-term potentiation in two groups of hippocampal neurons: control and treated. You induce lasting LTP in the control cells after repetitive high-frequency stimulation. In the treated cell, however, the potentiation begins to decrease after 2 hours. What treatment was given?

A) A drug that opens calcium channels

B) A drug that binds magnesium

C) A drug that inhibits protein synthesis

D) A drug that blocks clathrin

E) A drug that blocks sodium channels

C) A drug that inhibits protein synthesis

What triggers LTD?

A) High-frequency stimulation

B) Low-frequency stimulation followed by small or slow increase in Ca 2+

C) Ca 2+ influx into the postsynaptic terminal

D) Low-frequency stimulation followed by sharp and dramatic increase in Ca 2+

E) Internalization of AMPA receptors

B) Low-frequency stimulation followed by small or slow increase in Ca 2+

Which of the following statements is true about short-term synaptic plasticity?

A) Synaptic depression results from the build up of calcium in the presynaptic cell

B) Synaptic facilitation results from the build up of calcium in the postsynaptic cell

C) Synaptic facilitation results from the build up of sodium in the postsynaptic cell

D) Synaptic facilitation results from the build up of calcium in the presynaptic cell

E) Synaptic depression results from the build up of calcium in the postsynaptic cell

D) Synaptic facilitation results from the build up of calcium in the presynaptic cell

Which mechanism used in hippocampal LTD is not part of the hippocampal LTP mechanism?

A) Calcium-dependent activation of protein kinases.

B) NMDA receptor activation

C) Calcium-dependent activation of protein phosphatases

D) Calcium influx

E) History-dependent modification of synaptic efficacy

C) Calcium-dependent activation of protein phosphatases

What is the mechanism of LTP expression on time scales of seconds to minutes?

A) Increase in the number of presynaptic AMPA receptors

B) Increase in the intracellular level of synaptotagmins

C) Increase in the number of postsynaptic AMPA receptors

D) Decrease in the level of glutamate released into the synaptic cleft

E) Increase in the number of postsynaptic NMDA receptors

C) Increase in the number of postsynaptic AMPA receptors

What effect would a protein kinase inhibitor have on plasticity within the mammalian hippocampus?

A) It would enhance LTP

B) It would disrupt both LTP and LTD

C) It would enhance both LTP and LTD

D) It would disrupt LTD

E) It would disrupt LTP

E) It would disrupt LTP

How is 5HT involved in short term sensitization in Aplysia?

A) Binding of 5HT to K+ channels causes them to close

B) Binding of 5HT to GPCRs triggers a second messenger cascade that makes it harder to open K+ channels

C) Binding of 5HT to GPCRs triggers a second messenger cascade that increases the amount of glutamate packaged into individual vesicles

D) Binding of 5HT to calcium channels causes them to stay open for longer

E) Binding of 5HT to K+ channels causes them to open

B) Binding of 5HT to GPCRs triggers a second messenger cascade that makes it harder to open K+ channels

Which statement about long-term synaptic plasticity is false?

A) The tracking of long-term changes in synaptic efficacy is difficult in mammalian systems because of the complexity of mammalian brains.

B) The efficacy of transmission at many synapses depends on their history of synaptic activity.

C) The gill withdrawal reflex in Aplysia can be enhanced by pairing a noxious stimulus with a mild touch.

D) Gill withdrawal behavior in Aplysia can be altered for days or weeks by means of repeated pairings of shocks and touches.

E) Associative learning in the Aplysia gill withdrawal reflex is relatively independent of the timing or the order in which different stimuli are applied.

E) Associative learning in the Aplysia gill withdrawal reflex is relatively independent of the timing or the order in which different stimuli are applied.

Which of the following structural modifications accompanies the late phase of LTP?

A) Shrinkage of dendritic spines

B) Pruning of dendritic trees

C) Growth of dendritic spines

D) Shrinkage of axonal terminals

E) Growth of axon collaterals

C) Growth of dendritic spines

What is a silent synapse?

A) A synapse that only contains NMDA receptors

B) A synapse that transmits information in the absence of an action potential

C) A synapse that lacks mGluRs

D) A synapse that lacks calcium channels

E) A synapse that only contains AMPA receptors

A) A synapse that only contains NMDA receptors

What is plasticity?

how network shapes itself in response to experience to do better (learning, memory, brain development)

What is habituation?

decreased synaptic strength in response to a synapse caused by synaptic depression

What is sensitization?

short or long term increased synaptic strength caused by synaptic potentiation

Give an example of short term and long term potentiation

Short term- cAMP/PKA mediated change in K+ channels

Long term- CREB-dependent changes in protein synthesis

Define short term plasticity (facilitation/depression)

Temporary increase or decrease in strength of EPSC/IPSCs due to non-equilibrium conditions of presynaptic mechanisms

Define long term plasticity (LTP/LTD)

Long term changes in strength of a given input that is reflected in physical changes at the synapse (including protein expression -> larger/smaller areas)

Why does synaptic depression occur?

Vesicles are depleted from the RRP (readily releasable pool) so less transmitters are released temporarily until the pool is refilled and vesicles become available

Why does synaptic facilitation occur?

Presynaptic calcium builds up because the neuron is continually stimulated which leads to more vesicles being released

What is associative plasticity?

Cells that fire together, wire together- connections between pre and post neurons will increase, allowing the brain to better predict when a particular outcome may occur (like classical conditioning)

What is Hebb's postulate?

cells that fire together wire together/ classical conditioning is based in neurons

What is the hippocampus important in the formation of?

Memories! Removal/damage to hippocampus hurts long term memory

How would you measure the synaptic strength/plasticity of the hippocampus?

Use two electrodes (because the fibers in the hippocampus are so close together) and put them between the CA1 and CA3 axons. Stimulate the neuron near the CA3 neurons and record the response near the CA1 neuron with current clamp

What is tetanic stimulation?

100 Hz of presynaptic stimulation for 1 second to create plasticity (synapse 1 will increase and synapse 2 will remain the same)

Describe what synaptic plasticity means, and then, briefly, why it is important to study.

Synaptic plasticity refers to the ability of chemical synapses to undergo changes in strength of synaptic transmission. Changes in the strength and overall connectivity within the nervous system is important for much of brain development and underlies memory and the ability to learn.

Insertion of AMPA receptors into the postsynaptic membrane. LTD, LTP, both, neither?

LTP

Removal AMPA receptors from the postsynaptic membrane. LTD, LTP, both, neither?

LTD

A long-lasting decrease in synaptic strength. LTD, LTP, both, neither?

LTD

A long-lasting increase in synaptic strength. LTD, LTP, both, neither?

LTP

Late phase includes changes in gene expression and in the synthesis of proteins. LTD, LTP, both, neither?

Both

Occurs due to large and fast increase of postsynaptic Ca2+. LTD, LTP, both, neither?

LTP

Occurs due to small and slow increase of postsynaptic Ca2+. LTD, LTP, both, neither?

LTD

Requires NMDA-R mediated ion currents. LTD, LTP, both, neither?

Both

Requires postsynaptic hyperpolarization. LTD, LTP, both, neither?

Neither

Explain how NMDA-Rs mediate LTP in the mammalian hippocampus. Focus only on the early phase of LTP.

NMDA-Rs are responsible for coincidence detection, such that only coincidence pre- and postsynaptic activity lead to Ca2+ entry. Presynaptic activity releases glutamate and opens the channel, but no Ca2+ will flow without coincident postsynaptic depolarization, which removes the Mg2+ block.

Describe an experimental manipulation that could determine the critical role of NMDA-Rs in mediating LTP.

Using an NMDA-R antagonist (such as AP5) during a standard LTP stimulation paradigm (such as tetanic stimulation) will prevent LTP. Once the antagonist is washed out, LTP can then be induced using the same protocol (as a control). This will show that NMDA-Rs are necessary for LTP to be induced

Explain the role of AMPA receptors in LTP and LTD. There are at least two roles one can mention, but focus on how AMPA receptors are related to the strength of the synapse.

An increase in the number of AMPA receptors onto the postsynaptic membrane leads to the strengthening synaptic transmission of LTP due to a greater response of the postsynaptic cell to glutamate from the presynaptic cell, making the synapse stronger. Conversely, a decrease in the number of AMPA receptors on the postsynaptic membrane is associated with LTD, where the synapse is correspondingly weakened.

[Extra] Phosphorylation and dephosphorylation of AMPA receptors already in the membrane can increase and decrease, respectively, their peak conductance when they are open.

[Extra] AMPA receptors also play a role in depolarizing the neuron in the first place, which is necessary for LTP and LTD to be initiated through NMDA-dependent processes.

What is a silent synapse? Why is it called 'silent'?

A silent synapse is one that has NMDA receptors but no AMPA receptors. They are 'silent' because they do not respond to presynaptic glutamate release (because the Mg2+ block in the NMDA receptor is still present when the postsynaptic neuron is not depolarized).

Describe a synapse where LTP and LTD has been well studied, and then describe the patterns of presynaptic electrical stimulation that can induce LTP at that synapse.

LTP and LTD have been well studied at the synapse between the Schaffer collaterals (i.e. axons of CA3 neurons) and CA1 neurons in the mammalian hippocampus. Tetanic stimulation (100 Hz for ~1 second) of the presynaptic inputs can induce LTP at this synapse.

Describe how the above paradigm that you chose could be modified to instead induce LTD.

Stimulating the same synapse at 1 Hz for 15 minutes can induce LTD

Describe how the differences between the two types of stimulation results in the induction of LTP versus LTD.

Tetanic stimulation leads to the summation of EPSPs, which strongly depolarizes the postsynaptic cell during the period of stimulation, and leads to a large, relatively brief increase in Ca2+ levels in the postsynaptic neuron. This will preferentially drive phosphorylation of CaMKII (via calcium-calmodulin). CaMKII will phosphorylate many downstream substrates, but most significant is AMPA receptors, which causes them to be trafficked to the membrane.

Slow 1 Hz stimulation over 15 minutes only slightly depolarizes (the EPSPs won't sum) the postsynaptic neuron, and leads to a small, long-term increase in Ca2+ levels, which preferentially activates phosphatases (specifically, PP1), which dephosphorylates CaMKII as well as AMPA receptors, reversing the process described above.

The key here- tetanic stimulation generates large quick calcium influx which activates kinases, leading to AMPA-R insertion; slow stimulation generates slow small calcium influx which activates phosphatases, leading to AMPA-R removal.

List two reasons that Aplysia californica is a great model organism for studying synaptic plasticity.

Aplysia californica have large neurons, so they're accessible for study.

Aplysia californica have few neurons, so it's easier to understand how plasticity at a specific synapse can give rise to changes in behavior.

[Extra: Aplysia californica have neurons that are in stereotyped locations, so it's easy to find and study the same synapse in different subjects]

Explain what sensitization is, why it's important, and how it affects the gill withdrawal reflex of Aplysia californica.

Sensitization is when an organism becomes more responsive to a sensory stimulus. Long-term sensitization can be thought of as a simple form of associative learning. For example, in an Aplysia californica that has already undergone habituation, a light touch to the siphon will not produce gill withdrawal. However, repeated pairing of electrical stimulation of the tail with a light touch of their siphon ultimately results in a strong gill withdrawal even when only the siphon is lightly stimulated. In this case, the organism has learned that a light touch to the tail is associated with a noxious stimulus (tail shock).

Serotonin released by modulatory interneurons binds to _______ on presynaptic terminals of siphon sensory neurons.

G protein coupled receptors

This leads to the production of the secondary messenger, _____

cAMP

cAMP binds to the regulatory subunits of ______, releasing catalytic subunits , which ______ different proteins

PKA, phosphorylates

This decreases the probability that ____ channels will open during presynaptic action potential.

K+

A prolonged action potential results in the opening of more ____ channels

Ca2+

This increases the amount of _____ released onto the motor neuron

glutamate

List the similarities between sensitization in Aplysia and LTP in the mammalian hippocampus. In other words, identify how the two molecular pathways underlying each are similar.

- Both include an early phase that is characterized by protein kinases making posttranslational changes to plasma membrane ion channels. - Both also include a longer-lasting late phase where changes in gene expression and protein synthesis occur through mediation by CREB. - Both are likely to be involved in long-term storage of information.