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+ BIOL 371 > Lecture 15: Long Lasting Potentiation – Maintenance > Flashcards

Lecture 15: Long Lasting Potentiation – Maintenance Flashcards

1
Q

What is maintenance of potentiation?

A

describes alterations that persist for more than a day

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2
Q

How can we determine how potentiation is maintained over days, weeks or even years in Aplysia?

A

examine the induction and expression mechanisms that convert sensitization lasting hours to sensitization lasting days

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3
Q

How can we determine how potentiation is maintained over days, weeks or even years in the mammalian hippocampus?

A

examine how to induce or convert LTP into forms that lasts for days and weeks, rather than hours

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4
Q

What is spaced training?

A

repeated learning events separated (spaced) in time

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5
Q

What is massed training?

A

repeated learning events that occur back to back (en masse)

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6
Q

Is repeated or massed training more effective?

A

spaced training is more effective at producing long-term retention of both skills and information

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7
Q

Behavioural Correlates of the Induction of Long-lasting Sensitization – Aplysia

What does repeating a weak sensitization stimulus (tail shock) multiple times enhance?

A

enhances the withdrawal response, especially if the repetitions are spaced (separated in time), rather than massed (all at once)

  • spaced training leads to a response that is maintained (persists above baseline) for many days
  • massed training leads to a larger increase in magnitude of the response to the original test stimulus

note: in fictive sensitization paradigms, repeated applications of serotonin produce a longer lasting form of sensitization

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8
Q

Behavioural Correlates of the Induction of Long-lasting Sensitization – Aplysia

What does repeating a weak sensitization stimulus (tail shock) multiple times enhance?

A

enhances the withdrawal response, especially if the repetitions are spaced (separated in time), rather than massed (all at once)

  • spaced training leads to a response that is maintained (persists above baseline) for many days
  • massed training leads to a larger increase in magnitude of the response to the original test stimulus

note: in fictive sensitization paradigms, repeated applications of serotonin produce a longer lasting form of sensitization

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9
Q

What do you predict the response curve over 8 days would look like for true massed training (16 trials on one day)?

A

curve will start off high and continue to decrease linearly throughout the 8 days

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10
Q

Role of Transcription, and Translation in Memory Maintenance in Aplysia

What does the persistence of sensitization depend on?

A

de novo gene translation and transcription

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11
Q

Role of Transcription, and Translation in Memory Maintenance in Aplysia

What is the role of transcription and translation in short-term sensitization (lasting 1 to a few hours)?

A

translation and transcription are NOT necessary for sensitization’s induction or expression

  • short-term sensitization is not affected by blocking translation or transcription during training
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12
Q

What is required for maintenance of synaptic plasticity over hours to days?

A

gene expression

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13
Q

What part of memory is gene expression necessary for?

A

results of experiments blocking gene transcription and protein translation in Aplysia suggested that gene expression is NOT necessary for initial expression of short-term memory, but IS necessary for maintenance of long-term memories

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14
Q

What are third messengers?

A

molecules that enter nucleus and interact with DNA (DNA-binding proteins/transcription (co-)factors)

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15
Q

What do third messengers do?

A

link transduction cascades to gene expression mechanisms

  • gene expression
  • protein synthesis
  • global structural changes
  • global metabolic changes
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16
Q

What activates third messengers?

A

strong activation of signalling cascades

ie. cAMP response-element binding protein (CREB) – active in long term memory in Aplysia

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17
Q

Third Messenger: CREB Cascade

A
  1. second messenger cAMP activates PKA
  2. if sufficiently stimulated for a prolonged period of time (by repeated additions of serotonin), activated PKA will translocate to cell nucleus
  3. PKA phosphorylates CREB in nucleus
  4. phospho-CREB acts as transcription factor and joins another protein CBP/P300 (or C/EBP in Aplysia) to induce transcription of a particular set of genes (those containing the CRE promoter element)
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18
Q

What are immediate early genes (IEGs)?

A

genes that are transcribed and translated within ~90min of the activity signal

many are transcription factors, and therefore create transcription cascades

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19
Q

What does activity-induced transcription lead to?

A

new proteins being trafficked to the axon terminal

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20
Q

How is synaptic activity triggering gene expression changes?

A

activation of third-messenger-based signalling leads to a nucleus-to-synapse loop which stabilizes the original synaptic enhancement so that it can be maintained over long periods

  • third messenger activation (phosphorylation of CREB) induces gene transcription cascade through expression of IEGs
  • C/EBP is an example of IEG transcribed through p-CREB binding, which then acts to enhance further gene transcription
  • newly synthesized structural and regulatory proteins are trafficked down the axon, back to activated terminals, leading to persistent increases in their ability to release neurotransmitter without ongoing 5-HT signalling
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21
Q

What is long-lasting sensitization associated with?

A

synaptic enlargement and synaptogenesis

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22
Q

What genes are expressed to alter synaptic strength?

A
  • between IEGs and their immediate targets, it’s in the 100s – don’t need to remember full list of all genes in Aplysia that are expressed following p-CREB activation
  • focus on effects at the level of neurites and synapses
23
Q

Long-lasting sensitization is associated with synaptic enlargement and synaptogenesis.

A
  • in sensory neurons that have undergone long term sensitization, axonal arborizations (ie. number of axon branches) are greatly expanded (indicating increased numbers of structural/scaffolding proteins)
  • sensory neurons filled with fluorescent dye show varicosities (swellings where axon terminal specializations occur)
  • there are also many more synaptic varicosities (axon terminals) found on sensory neuron axons following sensitization (indicating increased numbers of axon terminal/active zone proteins)
24
Q

Invertebrate Memory Models – Convergence on Maintenance Mechanisms

What is they key idea?

A

two entirely different experimental approaches in unrelated species (Drosophila and Aplysia) both found that forms of memory lasting longer than a couple of hours make use of nuclear signalling and gene transcription mediated by cAMP/CREB third messenger pathways

25
Q

What is a tetanus/tetani?

A

trains of stimuli

26
Q

What is a (theta) burst stimulation?

A

bursts of stimuli – mimics the actual burst-and-pause firing patterns of working hippocampal neurons in vivo

27
Q

Can LTP in the mammalian hippocampus be maintained for more than a few hours?

A
  • repeated exposure to inducing stimuli (in this case, tetani), enhances magnitude of LTP
  • using patterns of spaced, repeating burst stimulation leads to even higher LTP magnitude in the first few hours after HFS

but would that advantage for spaced burst stimulation persist?

28
Q

What is the most effective stimulus for inducing stable LTP?

A

spaced and repeated TBS

  • on day 1: 20T and 4*5T stimulation induced similar amounts of LTP
  • on day 2: 4*5T stimulation induced a much larger amount of LTP
29
Q

What does maintenance of LTP for more than 1 hour depend on?

A

protein synthesis

including a blocker of protein synthesis during or just after induction of LTP does not prevent induction or alter initial magnitude of LTP (expression), but it does prevent it from persisting for more than a few hours

30
Q

Some forms of LTP also require ___ for maintenance.

A

immediate de novo gene transcription

example:
- transcription inhibitor actinomycin does not interfere with induction of LTP, but does prevent LTP from persisting for more than 2 hours – as long as it was present when induction occurred
- if actinomycin is added after the first 2 hours, it no longer has any effect on maintenance of LTP

31
Q

What does LTP maintenance depend on?

A

early, immediate burst of gene expression

  • there is a critical window (~90 mins) occurring immediately after strong LTP induction where activity-induced gene transcription and protein translation necessary for the long-term maintenance of LTP occurs
  • at least for protein synthesis, the critical window is actually a little more complicated (and a little looser)
32
Q

What does LTP maintenance over days rely on?

A

IEG expression, including zif-268

33
Q

What genes are expressed to alter synaptic strength?

A

number of transcription factors (TFs) are among the IEGs that begin to transcribe in the critical window following LTP induction

34
Q

What does hippocampal-based memory maintenance over days rely on?

A

IEG expression

ie. water maze experiment

35
Q

Is zif268 necessary for LTP expression?

A

NO

  • in zif-knockout mice, right after and on the first day, they had exactly the same amount of LTP
  • expression describes how much LTP there is for the same stimulus
  • zif isn’t necessary for LTP expression, otherwise you’d see an effect on LTP expression
36
Q

Is zif268 necessary for LTP maintenance?

A

YES

  • if you remove zif (zif-knockout mice), LTP is not maintained
37
Q

Is zif268 sufficient for LTP maintenance?

A

NO

  • sufficiency experiment was not conducted
  • there are 100’s of other transcription factors – researchers could have found something similar in another transcription factor (if there are two factors that both need to be present to get maintenance, neither would be sufficient)
38
Q

What does transcription-mediated maintenance of LTP also depend on?

A

third messenger pathways – there is strong convergence in many of the known third messenger pathways that lead to gene transcription that maintains LTP in hippocampus and long-term sensitization in Aplysia

39
Q

Third Messenger Pathways

A
  • strong forms of induction (ie. repeated, spaced tetani) activate more protein kinases, including PKA
  • ultimately a variety of synaptic structural and regulatory proteins are trafficked back to recently active synapses, helping to stabilize early changes to spine size and AMPAR content
  • third messenger activation (ie. pCREB) induces IEGs and gene transcription cascade
40
Q

What does protein synthesis also maintain?

A

synaptogenesis and synaptic enlargement in LTP

  • imaging experiments of structure of hippocampal dendrites show that dendritic spine volume in stimulated synapses increases after LTP induction
  • new spine synapses can also emerge
  • stimulated synapses enlarge following theta-burst induction of LTP
  • unstimulated synapses on the same dendrite do not change size
  • like electrophysiological responses in LTP, these structural changes in spine volume are not maintained if translation is blocked in neuron (by anisomycin)
41
Q

What is a puzzle/mystery of LTP?

A

LTP is synapse specific, but hippocampal neurons have thousands of spine synapses on their dendrites

So how are proteins translated in the soma in response to third messenger signalling trafficked to the few specific stimulated spines out of thousands on the same dendrites? – tagging and capture question

42
Q

What are hippocampal dendrites are capable of?

A

local translation of proteins without the nucleus

43
Q

What is a puzzling phenomenon regarding protein translation and LTP maintenance?

A

protein translation was always required for all types of hippocampal LTP maintenance for several hours, but mRNA transcription was NOT always required for persistent LTP

this was solved when lab observed that translation-dependent LTP could occur in CA1 cell dendrites that had been severed from cell body (and therefore the nucleus where transcription occurs)

44
Q

What effect does actinomycin have on induced LTP?

A

no effect

45
Q

What effect does anisomycin have on induced LTP?

A

leads to rapid decay of induced LTP

46
Q

What does adding a protein called brain-derived neurotrophic factor (BDNF) do to LTP?

A

leads to a persistent enhancement of fEPSP (ie. LTP), but NOT if you add anisomycin

47
Q

Dendritic Protein Synthesis is Activity-dependent and Localized to Stimulated Synapses

How do you get activity-dependent protein synthesis without de novo gene transcription?

A

dendritic mRNA can be translated in an activity-dependent manner

  • there are ribosomes in dendrites and even within dendritic spines
  • some mRNAs (for a subset of postsynaptic genes, including AMPAR subunits), are packaged and trafficked along dendrites into dendritic spines where they persist for long periods

example: Ca2+ influx through NMDARs activates CaMKII, which phosphorylates a synaptic protein called CPEB, which then stops repressing translation of particular local dendritic mRNA

48
Q

Why are we careful not to directly claim that LTP was the mechanism of memory?

A

experiments show that there exists at least one group of synapses in hippocampus whose efficiency is influenced by activity which may have occurred several hours previously – a time scale long enough to be potentially useful for information storage

whether or not the intact animal makes use in real life of a property which has been revealed by synchronous repetitive volleys to a population of fibres the normal rate and pattern of activity along which are unknown, is another matter

49
Q

The idea that synaptic plasticity is the underlying mechanism of memory of has persisted, but this hypothesis hasn’t gone unchallenged. Which objections can be dealt with relatively easily?

A

objections that “LTP requires high frequency tetanus, which is an unnatural form of stimulation” can be answered by the fact that theta-burst stimulation (which was based on real patterns of hippocampal cell firing) is highly effective at inducing long-lasting LTP

50
Q

What are the criteria that the ‘synaptic plasticity is memory’ (SPM) hypothesis needs to prove?

A
  • detectability – observe specific LTP-like changes after learning
  • mimicry – make a false memory by changing synaptic weights
  • anterograde alteration – prevent induction of LTP/LTD to prevent learning
  • retrograde alteration – remove expression of LTP/LTD (or add extra random synaptic changes) to erase learning
51
Q

In Aplysia and many other models, memory persistence is prolonged by what?

A

repeated, spaced training

this phenomenon also occurs in synaptic analogs of memory, both in Aplysia and in LTP

52
Q

In both Aplysia and LTP models of synaptic ‘memory’, maintaining potentiation over more than a few hours requires what?

A

protein translation, and often mRNA transcription in the nucleus

synaptic activity is relayed to nucleus by third messenger pathways, typically by kinase activation

53
Q

What is long-term maintenance of synaptic potentiation associated with?

A

structural changes to synapses, and growth of new synapses between activated neurons

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