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Current - BFoMH [Private] > Learning, memory and synaptic plasticity > Flashcards

Learning, memory and synaptic plasticity Flashcards

1
Q

What are the possible fluctuations of synaptic transmission?

A
  • Can increase or decrease
  • Can be short-lasting or long-lasting
  • We distiguish
    • Long term potentiation (LTP)
    • Long term depression (LTD)
    • Short term potentiation (STP)
    • Short term depression
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2
Q

What is the neurotransmitter involved in the plasticity of excitatory synaptic transmission?

A

Glutamatergic synapses, specifically NMDA receptors

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3
Q

What does the ‘tri-circuitry’ in the hippocampus refer to?

A
  • Granule cells in dentate gyrus have axons with mossy fibres
  • Perforant pathways come from entorhinal cortex and innervate granule cells
  • Mossy fibres innervate CA3 pyramidal neurons, which send their axons to Schaffer collaterals on CA1 pyramidal neurons
  • Synaptic plasticity has been studied between CA3 and CA1 neurons only
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4
Q

How is synaptic plasticity measured in the hippocampus?

A

By using electric stimulation electrodes that stimulate and record synaptic currents: evoking action potentials on axons

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5
Q

What did we learn from the H.M. patient regarding memory?

A

Patient with severe epilepsy
> Surgeons (1950s) lesioned the brain area causing the epilepsy, including the hippocampus
> Lesion was an effective treatment but resulted in severe memory impairment

=> Hippocampus is important for learning and memory, particularly for declarative memory

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6
Q

What is common to short term and long term potentiation?

A

Both require an increase of EPSP (excitatory postsynaptic potential) ~ high frequency stimulation

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7
Q

How does short term potentiation differ form long term potentiation and long term depression?

A
  • STP: lasts normally for about 30 minutes
  • LTP:
  • requires a higher frequency stimulation
  • can last for several hours or even up to a year (in vivo)
  • transient increase
  • LTD:
  • low frequency stimulation
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8
Q

Why is there a transient increase in LTP?

A

Because there is a post-tetanic potentiation and STP (short term potentiation) that precedes LTP

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9
Q

What are the phases of LTP?

A
  • Induction -> high frequency stimulation (e.g. 100 Hz = 100 stimulations/sec.)
  • Post-tetanic potentiation (PTP)
  • Short-term potentiation (STP)
  • Maintenance
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10
Q

What are the properties of LTP?

A
  • Long lasting
  • Input specific
  • Cooperativity
  • Associativity
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11
Q

What makes LTP long lasting?

A

Long lasting enhancement of synaptic transmission

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12
Q

What makes LTP input specific?

A

LTP is specific to the activated synapses and doesn’t affect neighbouring synapses

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13
Q

What is the cooperativity property of LTP?

A

A threshold stimulation is required to induce LTP - only signals of relevance induce LTP

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14
Q

What is the associativity property of LTP?

A

One synapse undergoing weak stimulation (not sufficient to induce LTP) can be converted into an LTP inducing stimulation when a neighbouring synapse experiences LTP induction

  • weak stimulation + strong stimulation = LTP induced
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15
Q

What are the receptors underlying LTP induction?

A

Glutamatergic synaptic transmission

  1. AMPA receptors
    - main carriers of Glu transmission
    - depolarises postsynaptic membrane
  2. NMDA receptors
    - requires a Mg2+ release and post-synaptic depolarisation to open
    - > Ca2+ influx -> bind to calmodulin -> protein kinase activation -> synaptic changes

=> Signalling cascade -> gene expression changes in the nucleus or translation of mRNA at the synapse
-> synthesis of new proteins

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16
Q

Why do NMDA receptors require a Glu release and post-synaptic depolarisation to open?

A

Because they’re blocked by Mg2+ ions that can only be removed by depolarisation

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17
Q

What are the molecular mechanisms through which synaptic transmission in the postsynaptic membrane can be enhanced, to induce LTP?

A
  1. Phosphorylation of the AMPA receptors
    - > increase their conductivity = more Glu neurotransmission -> more depolarisation -> more ions fluxing in
  2. Increased numbers of AMPA receptors generated by endosomes (in postsynaptic membrane) that can be fused with the membrane
  3. Retrograde signalling:
    - signal from post-synapse to presynapse -> modifies presynaptic Glu NT release
    - e.g. nitric oxide gas is a retrograde signal: diffuses from postsynapse to presynapse
    - > enhanced NT release
18
Q

What is the role of CaMKII in LTP induction?

A

Calcium calmodulin-dependent kinase II (CaMKII)

  • phosphorylates itself
  • can phosphorylate AMPA receptors
  • > AMPAR can be trafficked into the postsynaptic density

=> CaMKII seems to be a critical enzyme for the induction of LTP

19
Q

Who introduced Late-LTP?
What is required for LTP to become Late-LTP (L-LTP)?

A

Terminology by Eric Kandel:
LTP requires gene transcription and protein synthesis to be long lasting -> Late-LTP (L-LTP)
- the proteins required for the induction of LTP also contribute to its long lasting nature

20
Q

How can the new synthesised proteins be delivered specifically to the synapses undergoing long term potentiation, and produce Late-LTP?

A 
Synaptic tagging (synaptic capture): 
1. Signals reaches nucleus -\> gene expression, mRNA translation and protein synthesis
  1. Importins seem to be important molecules for gene expression
  2. The newly synthesised proteins can only be taken up by tetanised (stimulated) synapses
  3. Strong tetanisation induces a molecular change: Tag Setting, that captures plasticity-related proteins (PRPs)
    - > taking up PRPs allows LTP to be developed into L-LTP
  4. Late phase LTP
  5. Early phase LTP in neighbouring pathway transforms into Late-LTP due to it coinciding in time with a strong tetanisation
21
Q

What is the process behind LTP maintenance?

A

> Suggested to be mediated by the local translation of the protein kinase M zeta (PKMζ)

> PKMζ lacks a regulatory domain -> its catalytic domain is active overtime once it has been produced

> PKMζ mRNA is translationally repressed
-> when Late-LTP is induced, repression is relieved and PKMζ mRNA can be translated

-> PKMζ is active overtime and promotes trafficking of AMPAR -> maintains high density of AMPAR

=> This mechanism only lasts for as long as PKMζ is around

22
Q

How is LTP kept over a lifetime?

A

> Once PKMζ is turned over, it is replaced by newly synthesised PKMζ
> An active form of PKMζ should always be present in the synapses that maintain LTP

23
Q

What are the forms of memory associated with the hippocampus in humans and mice?

A

> Humans: hippocampus associated with declarative memories (not applicable to mice)

> Mice: hippocampus associated to spatial and contextual memory

24
Q

What the American-British neuroscientist John O’Keefe discover?

A

The importance of the hippocampus in the process of making spatial map of the environment: ‘cognitive map’

25
Q

What did the study on learning in the Morris water maze with mutant mice vs. wild type mice show (Need and Giese, 2003)?

A

> Wild type mice showed improvement in learning over time
> Mutant mice did not show improvement

> Training curve alone does not suffice as indicative of impaired spatial learning in the mutant mice or of spatial learning in wild type mice
- mice might be using alternative strategies

  • > memory prove trial that indicates different strategies:
  • learning that there’s no escape
  • use of platform
  • strategy learning
  • spatial strategy
26
Q

What did the water maze spatial memory probe trial with drug treated mice vs. control mice show (Morris et al., 1986)?

A

> Amount of time spent by control mice in training quadrant indicates:

  • clear spatial bias
  • evidence for spatial memory

> Amount of time spent by drug treated mice in training quadrant indicates:
- lack of spatial memory (random search of platform in the pool)

> Drug treated mice (AP5: NMDAR blocker)
-> blocking NMDA receptor impairs spatial learning

> Drug was relatively high -> performance abnormalities in some animals
-> blocking NMDA receptors not only blocks LTP but also blocks long term depression

27
Q

What does the passive avoidance task consist of?

A

> Mice learn that going in the dark compartment, they receive a mild electric foot shock -> learn to avoid the dark

> Can be learned in a single trial

> Task requires the hippocampus

28
Q

What would a lesion in the hippocampus cause in the passive avoidance task?

A

It would jeopardise the mouse’s association between the dark compartment the foot shock

29
Q

What are the advantages of the one-trial learning task?

A

> Useful in the study of molecular and cellular processes due to animals all learning at the same time

> More suitable in the study of learning and memory processes vs. water maze where there’s lack of synchronisation in animal behaviour
-> more noise in analysing molecular and cellular mechanisms

> Easy to distinguish short term memory (e.g. 30 min) and long term memory (24h)

30
Q

What did the passive avoidance one-trial learning task show (Irvine et al., 2005)?

A

> Wild-type animal avoids dark compartment (spends more time in lit compartment)

> Mutant animal: hippocampal process is impaired in both long term (24h) and short term (30 min) memory
- doesn’t remember receiving the shock in the dark compartment so it’s still motivated to go there

31
Q

What is Donald Hebb’s postulate?

A

“When an axon of neuron A excite(s) neuron B and repeatedly […] takes part in firing it, some growth processes or metabolic changes take place in one or both neurons so that A’s efficiency as one of the cell firing B is increased.”

32
Q

How does LTP follow Hebb’s postulate?

A

It is the synaptic transmission that is enhanced not the firing, when axon of neuron A excites neuron B and repeatedly participates in firing it

33
Q

Why are there multiple electrodes used to detect LTP?

A

Only a small number of synapses undergo LTP

34
Q

What did the inhibitory avoidance task show (Whitlock et al., 2006)?

A

> Only the synapses of trained animals show 150% EPSP slope ; never observed in naive animals

  • some synapses are severely potentiated: true for 30 min, 1 and 2 hours
  • > these synapses have produced LTP

> No LTP was induced in the performance controls
- no association between darkness and shock

> LTP was only induced only in animals trained in the inhibitory avoidance task
=> behavioural training can induce LTP

> LTP is NMDA receptor-dependent and occurs during memory formation

35
Q

What is the general strategy for gene targeting in mice?

A

Whilst a limited number of drugs allows to block particular molecules, genetics allow us to manipulate any gene of interest

36
Q

What is the rationale of gene targeting in mice, in the study of LTP?

A

LTP can be blocked by generating mutant mice

  1. Impairment of the molecular process
  2. Impairment of LTP
  3. Impairment of learning and memory
37
Q

For which discovery did Susumu Tonegawa receive the Nobel Prize?
What were his method of study and result?

A

Discovery of antibody diversity

> Method of study: region-specific knockout mice
- knock out an essential NMDA receptor subunit (GluN1) exclusively in the hippocampus, and study its impact

> Result:

  • Succeeded in having a mutant mouse with an active Core recombinase exclusively in the CA1 hippocampal area
  • > knocking out the gene that encodes GluN1 blocks NMDA receptors
38
Q

What is the impact of blocking NMDA receptors in CA1 hippocampal area on spatial memory?
What is this consistent with?

A

Knocking out NMDA receptors in the CA1 impairs spatial learning

  • findings consistent with pharmacological blockage of NDMA receptors resulting in blockage of spatial memory
  • > impaired LTP induction impairs spatial memory

> However, NMDA receptors can also block long-term depression

39
Q

What was the basis of the interest to make a mutation that blocks for the autophosphorylation of CaM Kinase II?

A

CaMKII is dependent on high levels of Ca2+
-> when Ca2+ levels drop back to baseline, enzyme is inactive

> However, CaMKII can phosphorylate itself at threonine-286, which is within the regulatory domain

    • phosphorylation at threonine-286 = further conformational change that entraps the bound calcium calmodulin
  • > at baseline levels, there is still bound calcium calmodulin -> enzyme remains active

> Autophosphorylation event thought to be an important event for maintaining LTP

40
Q

What did the study with a mutant mouse that has threonine-286 change to alanine show?

A

> Alanine cannot be phosphorylated ; doesn’t have a hydroxyl group
= block the autophosphorylation at threonine-286

-> CaM Kinase II that is normally active with a presence of calcium calmodulin

=> Autophosphorylation of CaMKII at threonine-286 I fundamentally important for the induction of LTP

41
Q

What did the study on impaired spatial learning and memory in T286A mutants show?

A

Memory probe trial
> Wild-type animals have a selective surge in target quadrant
> Mutant animals have random surge -> no spatial memory

> Mutants lack LTP induction and spatial memory
-> LTP induction correlated to spatial memory formation

42
Q

What did the study on ZIP treated animals show (Pastalkova et al., 2006)?

A

> ZIP erased the memory of animals -> erased LTP
-> strong correlation between LTP and memory maintenance

> ZIP: peptide that blocks protein kinase M zeta
- ZIP blocks LTP maintenance mechanism, via PKMzeta

> However it has bee shown that when PKMzeta is knocked out in mice, ZIP is still able to block LTP maintenance
-> ZIP might also act directly on our molecules, not rely on PKMzeta

> ZIP induced loss of spatial avoidance memory

  • animals injected with ZIP -> no memory
  • animal is caught almost-immediately back in the danger zone

=> Blocking LTP maintenance seems to erase spatial memory

Current - BFoMH [Private] (15 decks)

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