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PMCOL 371 - Cellular Neuroscience > 15 - LTP and Memory > Flashcards

15 - LTP and Memory Flashcards

1
Q

“Mental exercise facilitates a greater development of … the nervous collaterals in the part of the brain in se. In this way, preexisting connections between groups of cells could be reinforced”

Modern parlance?

A

Strengthening of synapses may occur as a mechanism for learnign

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2
Q

Cells that fire together, wire together. What molecular basis for this idea was shown?

A

NMDA receptor - coincidence detector at synapses

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3
Q

The hippocampus is critical for what process (memory)

A

Memory consolidation

converting STM into Long term memory

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4
Q

IMAGE SLIDE 4 (?)

How is long term memory classified?

A

Long term memory

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5
Q

Hippocampal neurons can act as ____ cells

A

Hippocampal neurons can act as place cells

-regions of space in which the cell shows preferential firing (ie fire when animal is in a specific location)

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6
Q

Four functions of the hippocampus

A
  1. memory formation
  2. spatial learning and spatial memory
  3. non-spatial learning such as visual recognition of objects
  4. forming associations between events occurring in close temporal succession to each other
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7
Q

2 hypotheses for hippocampal fxn

A
  1. cognitive map theory
    1. you are here and not there
  2. Relational memory theory
    • you are here in respect to other areas
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8
Q

What is long-term potentiation?

A

Brief bursts of high frequency stimuli caused a long-lasting increase in the size of subsequent EPSPs

ie synaptic strength increases instantaneously and stays increased for several hours - summation

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9
Q

What is long term depression?

A

Activity dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long-patterned stimulus

occurs when postsynaptic spikes precede presynaptic spikes by up to 20-50ms

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10
Q

properties of LTP

A
  1. Cooperativity
    • Need to activate enough afferent fibers (presynaptic axons) to elicit LTP
  2. Associativity
    • Pairing stimulation of weak and strong pathways elicits LTP
  3. Specificity
    • LTP is restricted to the stimulated pathway
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11
Q

how to record ltp

A

take baseline (20-30min)

pause stimulator

use pulse or more of 100hz to give high freq stim

ltp characterized by sharp/sudden increase in EPSPs

long-lasting ltp depends on protein synthesis translation - linked to long term memory in mice

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12
Q

Mechanisms of LTP: Post-synaptic alteration

Key mechanism for LTP expression:

A

Trafficking of AMPA receptors

ie ampa receptors added to post-synaptic membrane = amplifies sound

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13
Q

Mechanisms of LTP: post-synaptic alteration

What happens during tetanus? (high freq stimulus)

A

Unblocking of NMDA receptors → entry of Ca++ into post synaptic dendritic spine → activates kinases such as CaMKII, PKC, tyrosine kinases PKA

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14
Q

Additional properties that makes LTP excellent synaptic mechanism for memory storage:

  • LTP is ______ (requires only a very brief burst of stimulation)
  • LTP is _______ (can last for up to a year in intact lab animals)
  • LTP-like plasticity occurs during _______
  • Signaling requirements for _______ mirror those for LTP
  • Like long-term memory, LTP requires ________
A
  • LTP is rapidly induced (requires only a very brief burst of stimulation)
  • LTP is long-lasting (can last for up to a year in intact lab animals)
  • LTP-like plasticity occurs during associative learning
  • Signaling requirements for memory storage mirror those for LTP
  • Like long-term memory, LTP requires protein synthesis
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15
Q

2 Caveats to Ltp as synaptic mechanism for memory storage:

A
  • LTP is required, but is not sufficient, for some forms of learning and memory.
  • LTD is also critical for some forms of learning and memory, such as spatial memory formation in the water maze.
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16
Q

LTP and LTD induction involve different levels of ______ influx

A

LTP and LTD induction involve different levels of calcium influx

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16
Q

LTP and LTD induction involve different levels of ______ influx

A

LTP and LTD induction involve different levels of calcium influx

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17
Q

DESCRIBE the IMAGE

high frequency stim (HFS) leading to LTP → substantial increase in __________ → activates a number of ________ → culminates in ___

In contrast:

Lower frequency stimulation (LFS) leads to a more modest increase in _____ → preferentially activates _____ which remove ______ from proteins and therefore favours ___

A

high frequency stim leading to LTP → substantial increase in post-synaptic calcium → activates a number of protein kinases which phosphorylate other proteins → culminates in LTP

In contrast:

Lower frequency stimulation (LFS) leads to a more modest increase in calcium → preferentially activates protein phosphatases which remove phosphate groups from proteins and therefore favours LTD

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18
Q

What is the most intensely studied excitatory synapse in the mammalian brain?

A

Schaeffer Collateral Pathway - extends from area CA3 to pyramidal neurons of area CA1 in the hippocampus

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19
Q

The Schaeffer collateral pathway extends from ____ to _____ in the hippocampus

A

Schaeffer Collateral Pathway - extends from area CA3 to pyramidal neurons of area CA1 in the hippocampus

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20
Q

How does Hippocampal LTP show cooperativity, associativity and input specificity?

A
  • Cooperativity:
    • The likelihood of inducing LTP increases when the number of stimulated fibres is increased
  • Associativity:
    • If two separate pathways (A and B) converging onto the same postsynaptic target cell are present, such that both can be stimulated to geve weak (A) and strong (B) inputs, then LTP can be induced in the weak pathway ONLY when its activity is associated or paired with activity from the strong pathway
  • Specificity:
    • LTP is evident only at activated synapses
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21
Q

What is typically measured during field potential recordings?

A

Initial slope of the EPSP

Voltage shown as downward deflection because tip of electrode is outside the cell

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22
Q

long-lasting ltp depends on _______ - linked to long term memory in mice

A

long-lasting ltp depends on protein synthesis translation - linked to long term memory in mice

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23
Q

All AMPARs consist of ____ subunits, usually a dimer of ____ plus a dimer of ____

A

All AMPARs consist of 4 subunits, usually a dimer of GluR2 plus a dimer of Glu⅓/4

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24
Q

Most AMPARs in the hippocampus contain ____ subunits

A

Most AMPARs in the hippocampus contain GluR2 subunits

GluR2 enables outward and inward currents to occur, depending on the membrane potential

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25
Q

Most AMPARs in the hippocampus contain GluR2 subunits

which enables:

A

Most AMPARs in the hippocampus contain GluR2 subunits

GluR2 enables outward and inward currents to occur, depending on the membrane potential

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26
Q

Activity induces insertion of _______ receptors which cause _____

A

Activity induces insertion of GluR1/GluR2 heteromeric receptors which cause LTP

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27
Q

Maintaining synaptic transmission at a given level involves replacing ________ receptors with ________

A

Maintaining synaptic transmission at a given level involves replacing GluR1-containing receptors with GluR2 containing receptors (eg GluR2/GluR3 heteromers)

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28
Q

AMPA receptors containing GluR1 help regulate ______ during LTP

A

AMPA receptors containing GluR1 help regulate insertion during LTP

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29
Q

Ampa receptors containing GluR2 control _____ of receptors

A

Ampa receptors containing GluR2 control removal/endocytosis of receptors = LTD

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30
Q

NMDA receptors have ___ subunits; in hippocampus consist of two mandatory _____ subunits combined with _____ and/or _____

A

NMDA receptors have 4 subunits; in hippocampus consist of two mandatory NR1 subunits combined with NR2A and/or NA2B

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31
Q

NMDA receptors with NR2A subunits are predominantly at the _______

And NR2B receptors are mainly located ______

A

NMDA receptors with NR2A subunits are predominantly at the synapse

And NR2B receptors are mainly located distal from synapses

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32
Q

Research has shown that NR2A receptors are needed for _______ whereas NR2B receptors are needed for _____

A

Research has shown that NR2A receptors are needed for LTP induction whereas NR2B receptors are needed for LTD

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33
Q

Not all forms of LTP share the same mechanisms. Eg LTP is known to consist of at least 2 temporal phases:

A

An early phase (E-LTP)

A late phase (L-LTP)

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34
Q

L-LTP but not E-LTP requires _______ and activation of _______ for its stable expression

A

L-LTP but not E-LTP requires protein synthesis (translation) and activation of cAMP-dependent protein kinase (PKA) for its stable expression

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35
Q

When would synthesis of new proteins and activation of genes be required?

A

Only long-lasting changes in synaptic strength require the synthesis of new proteins and activation of genes

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36
Q

Making new long-term but not short-term memories requires:

A

Neural protein synthesis

37
Q

L-LTP can last ______ and is induced by ______

E-LTP can last ______ and is induced by ______

A

L-LTP can last several hours in slices and is induced by strong electrical stimulation

E-LTP can last less than 2 hours and is induced by weaker stimulation

38
Q

L-LTP has been shown to be strongly correlated with ________ (memory)

A

L-LTP has been shown to be strongly correlated with consolidation of long-term memory (memory)

39
Q

LTP might be a neural representation of ______

A

long term memories

40
Q

What is induction?

A

induction refers to the initiating events that trigger LTP

41
Q

What processes are involved in induction?

A
  1. High frequency stimulation → releases glutamate from presynaptic terminals → binds to NMDA and AMPA receptors on surface of postsynaptic neurons → depolarization → relieves magnesium block of NMDA receptor channels → Ca++ passed into postsynaptic cell
  2. Entry of Ca++ into postsynaptic cell through voltage-gated ca++ channels and NMDA receptor channels required for induction of LTP
  3. Several protein kinases have been implicated in LTP induction
    • Ca/Calmodulin-depended protein kinase II (CaMKII) and protein kinase C (PKC)
    • Tyrosine kinases also seem to participate
42
Q
  1. Pharmacological block of _____ receptors by application of _________\_(such as ____\_)) prevents induction of LTP
  2. Valid for LTP at the _________\_of area ____\_ (high densities of NMDA receptors)
A
  1. Pharmacological block of NMDA receptors by application of NMDA receptor antagonists (such as D-2-amino-5-phosphonopentenoic acid (AP5/APV)) prevents induction of LTP
  2. Valid for LTP at the Schaeffer collateral synapses of area CA1 (high densities of NMDA receptors)
43
Q

What happens if calcium chelators are injected into postsynaptic cells?

A

induction of LTP is blocked → Ca++ entry into postsynaptic cell is required for induction of LTP

44
Q

What is a critical trigger for LTP?

A

Elevation of postsynaptic calcium

Injection of calcium into postsynaptic cells produces potentiation and blocking Calcium blocks LTP

45
Q

What Protein Kinases have been implicated in LTP induction?

A
  • Calcium/calmodulin-dependent protein kinase II (CaMKII)
  • Protein kinase C (PKC)
  • Tyrosine kinases
  • PKA
46
Q

How do we know that CaMKII and PKC are involved in LTP induction?

A

Because blockers of these kinases prevents induction and maintenance of LTP

47
Q

How do we know tyrosin kinases participate in LTP induction?

A

B/c pharmacological block of these kinases by a specific inhibitor of tyrosin kinases (genistein) prevents LTP induction

48
Q

How does PKA enable induction of L-LTP?

A

By inhibiting protein phosphatases q and 2A (PA1 /2A)

Phosphatases dephosphorylate proteins - known that phosphatase activation suppresses LTP and favors LTD

49
Q

By inhibiting PP1 /2A PKA allows L-LTP to be induced through suppression of

A

An inhibitory constraint exerted by these phosphatases

50
Q

PKA and MAP kinases (aka ERK) modulate the ________ to control ______ which is critical for _______

A

PKA and MAP kinases (aka ERK) modulate the translational machinery to control initiation of translation (protein synthesis) which is critical for initiating long-lasting potentiation

ERK = extracellular signal-regulated kinase

51
Q

Overall, phosphorylation of proteins in postsynaptic neurons by ______, ____, ____ and _____ is essential for induction of various forms of LTP

A

Overall, phosphorylation of proteins in postsynaptic neurons by CamKII, PKC, PKA, and tyrosine kinases is essential for induction of various forms of LTP

52
Q

What are 3 possible methods of expression?

A

Once LTP is triggered, the synaptic enhancement needs to be established or expressed:

  • Increased number of effective release sites in presynaptic terminals (uncovering of “silent” synapses after LTP induction)
  • Increased probability fo transmitter secretion because of AP broadening or enhanced excitation-secretion coupling in nerve terminals (presynaptic mechanism)
  • An increase in # of postsynaptic receptors and/or increased receptor sensitivity to transmitter
53
Q

Blocking ______ in hippocampal slices prevents expression of L-LTP

A

Blocking protein synthesis (translation) in hippocampal slices prevents expression of L-LTP

54
Q

What are two drugs that are used to block translation (and thus can prevent expression of L-LTP)

A

Anisomycin and cycloheximide

55
Q

Blocking transcription with an inhibitor (eg ______) prevents _______ without affecting induction of early-LTP. What does this suggest about transcription?

A

Gene expression (transcription is required for L-LTP

Blocking transcription with an inhibitor (eg actinomycin-D) prevents expression of L-LTP without affecting induction of early-LTP. What does this suggest about transcription?

56
Q

Regulating translation is important for controlling the ________

A

Regulating translation is important for controlling the persistence of LTP

57
Q

How is rapid, local control of long-lasting plasticity at individual synapses accomplished?

A

Plasticity-related proteins can be produced rapidly and locally (in dendrites) after electrical stimulation.

Dendritic expression of some proteins is increased within 5 min after LTP induction

This allows for rapid local control of long-lasting plasticity

58
Q

How to cells respond to external stimuli?

A

by regulating the translational efficiencies of specific mRNAs to synthesize proteins

59
Q

What is translation initiation

A

Translation initiation (TI) is rate-limiting and most translational control mechanisms act on TI

These predominantly involve the phosphorylation of “eukaryotic initiation factors” (eIFs) that assemble TI complexes that promote ribosomal binding to mRNAs - required step for TI

60
Q

How is TI measured?

A

The levels of expression of specific phopho-eIFs are used as measures of TI

(eIFs = eukaryotic initiation factors)

61
Q

What is one key rate-limiting step during TI

A

The ability of eIF4E to form eIF4F initiation complex

TI is facilitated by eIF4F

62
Q

What does eIF4F consist of and what binding is critical towards the formation of 4F complex and TI?

A

eIF4F consists of eIF4A, 4E, and 4G

4E binding to 4G is a critical step towards 4F complex formation and TI

63
Q

In the basal state, 4E is sequestered by an _________

A

In the basal state, 4E is sequestered by an inhibitory binding protein (4EBP)

64
Q

What increases 4EBP phosphorylation and what does it allow?

A

HFS-induced L-LTP increases 4EBP phosphorylation, which frees 4E to bind to 4G to form the 4F complex

65
Q

In mouse hippocampus, genetic deletion of an isoform of 4EBP, 4EBP2 increases _______ and converts ________ into persistent, translation-dependent L-LTP following just one 100Hz train

A

In mouse hippocampus, genetic deletion of an isoform of 4EBP, 4EBP2 increases 4F complex formation and converts short-lasting, translation-independent E-LTP into persistent, translation-dependent L-LTP following just one 100Hz train

66
Q

What would cause L-LTP induced by multiple trains of 100Hz stimulation to be reduced, along with reduced long-term fear memory?

A

Genetic deletion of an isoform of 4EBP (4EBP2) which would increase 4F complex formation

67
Q

In the mouse hippocampus, genetic deletion of an isoform of 4EBP, 4EBP2, increases 4F complex formation and converts short-lasting, translation-independent E-LTP into persistent, translation-dependent L-LTP following just one 100Hz train - reduces L-LTP induced by multiple 100Hz trains and reduced long term fear memory.

What does this indicate?

A

Indicates that increased translation initiation in 4EBP2 knockout mice is detrimental to this form of LTP and to long-term memory

Thus tight regulation of translation initiation is needed for normal expression of LTM

68
Q

Which two key kinases regulate 4EBP in hippocampal neurons?

A

ERK and mTOR (mammalian target of rapamycin)

69
Q

How does mTOR regulate 4EBP?

A

mTOR directly phosphorylates 4EBP to release 4E from repression and promote formation of 4F initiation complex

70
Q

What phosphorylates ERK and what does it allow?

A

MEK (MAPK/ERK kinase) phosphorylates ERK, which then phosphorylates (activates) Mnk1 (MAPK-interacting kinase-1)

71
Q

What is the function of Mnk1?

How is it activated

A

MEK phosphorylates ERK- phosphorylates (activates → Mnk1

Mnk1 phosphorylates 4E → promotes 4E binding to 4G → enhances formation of the 4F initiation complex

72
Q

______ gates ERK-dependent phosphorylation of 4E and translation initi

A

mTOR gates ERK-dependent phosphorylation of 4E and translation initi

73
Q

L-LTP is associated with regulation of a critical translation factor ______ by ERK and mTOR

A

L-LTP is associated with regulation of a critical translation factor eIF4E by ERK and mTOR

74
Q

L-LTP is associated with regulation of a critical translation factor eIF4E by ___ and ____

A

L-LTP is associated with regulation of a critical translation factor eIF4E by ERK and mTOR

75
Q

How are signalling pathways responsible for induction and expression of hippocampal LTP identified? (2 approaches)

A
  • Genetic approach
    • create genetically-modified mice with specific protein kinases or phosphatases knocked our or inhibited in their hippocampi
    • measure behaviour and synaptic physiology
  • Pharmacological approach
    • several drugs that inhibit specific biochemical signalling pathways (many are membrane permeable - easy to apply to hippocampal slices)
    • Block activation of specific protein kinases or protein phosphatases that are believed to be important for LTP induction or expression
76
Q

What are commonly used inhibitors of some protein kinases and phosphatases?

A
77
Q

What is the time difference between Amygdala fear conditioning and the hippocampus spatial learning?

A
  • Hippocampus and spatial learning
    • done with Morris maze
    • Takes weeks of training
  • Amygdala fear conditioning
    • remember task after just one session lasting about 3 minutes
78
Q

What area of the brain is required for fear conditioning?

A

the amygdala - lesions of the amygdala impair fear conditioning

79
Q

What part of the brain is required for making emotional memories?

A

Amygdala

80
Q

What experiment provided a convincing demonstration that LTP can occur in vivo during and after learning?

A

Recording EPSPs in the amygdala → these EPSPs became potentiated when auditory tone was paired with foot shock

Potentiation persisted after training

-unpaired random delivery of shock and tone resulted in less potentiation

Thus LTP in the amygdala can occur in awake rats as a consequence of behavioural learning and memory

81
Q

Strong stimulation (such as in long-term potentiation) preferentially activates:

A

PKA → carries out a number of processes including recruitment of transcription in nucleus / production of mRNAs → translated into proteins related to post-synaptic growth

82
Q

The ERK pathway is important for ______

A

Translation (protein synthesis)

83
Q

PKA suppresses ______

A

PKA suppresses PP1

-tips scale in favour of Ltp

83
Q

PKA suppresses ______ through inhibitor-1

A

PKA suppresses PP1

84
Q

PKA suppresses Protein Phosphatase-1 (PP1) through _______

A

PKA suppresses Protein Phosphatase-1 (PP1) through inhibitor-1

85
Q

Which promoter drives transgene expression in forebrain, hippocampus?

A

CaMK2-alpha promoter

  • produce transgenic mice that overexpress genes
86
Q

Antagonists to which receptor blocks water maze learning and hippocampal LTP?

A

NMDA Receptor Antagonist (DL-AP5)

87
Q

Contextual memory requires ____ and ____

A

Contextual memory requires hippocampus and amy

88
Q

Cued memory requires

A

the amygdala

89
Q

Which site of the amygdala is critical for integrating the CS (tone) and US (footshock)

A

Lateral nucleus of the amygdala

PMCOL 371 - Cellular Neuroscience (19 decks)

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