LTP Flashcards
(71 cards)
1
Q
Synaptic plasticity definition
A
Increasing (or decreasing) the functional connectivity between pre-synaptic and post-synaptic elements.
2
Q
Hebb’s (1949) idea on how memories are encoded and stored
A
Cells that fire together at the same time will become more connected with one another (compared to those that do not fire together).
3
Q
How many neurons are there in the human brain?
A
100 billion (10^11).
4
Q
How many synapses are there in the human brain?
A
100 trillion (10^14).
5
Q
What is a cell assembly?
A
A group of neurons that work together to represent a concept in teh brain.
6
Q
How can we study synaptic plasticity?
A
Some brain regions are strongly connected to other regions via axons that travel in bundles.
- Stimulating axons.
- Record close to the post-synaptic cells to compare input-output responses.
We can investigate input-output relationships at a
population level.
7
Q
What is the pathway into the hippocampus?
A
Entorhinal cortex -> dentate gyrus -> CA3 -> CA1.
Perforant path -> mossy fibres -> schaffer collateral.
8
Q
What did Lomo (1966) do?
A
Entorhinal cortex -> dentate gyrus. Stimulation trains in the perforant path.
- Magnitude of responses increased over the course of the train (80th pulse larger than the first).
- Magnitude of responses for subsequent trains also increased.
Stimulating axons through repetitive stimulation changed the magnitude of the field potential.
9
Q
Bliss and Lomo (1973) anaesthetised rabbit.
A
Stimulated perforant path (axons). Recorded dentate gyrus. Amplitude of EPSP got progressively larger in stimulated pathway.
- Test pulses to establish the baseline field potential.
- Stimulated at a high frequency (tetanus).
- Return to test pulses to see if new field potential is same as baseline.
10
Q
Bliss and Collingridge (1993) 3 properties of LTP
A
- Co-operativity.
- Input specificity.
- Associativity.
11
Q
Co-operativity
A
A single weak stimulus does not induce LTP but several
weak stimuli converging on one part of the post-synaptic membrane can induce LTP (surpass a threshold).
12
Q
Input specificity
A
LTP at one synapse does not cause LTP at other synapses.
13
Q
Associativity
A
A weak stimulus combined simultaneously with a strong stimulus on a different pathway can induce LTP at both pathways.
14
Q
Dudek and Bear (1992) repetitive low frequency (1Hz) stimulation
A
Reduces size of field potential (LTD; long-term depression).
15
Q
What receptors are required for LTP activation?
A
- AMPA.
- NMDA.
16
Q
What are the properties of AMPA?
A
- Ligand (chemical) gated.
- Requires glutamate to bind to it for it to open its pore.
- Only allows sodium into the post-synaptic cell.
17
Q
What are the properties of NMDA?
A
- Ligand + voltage gated.
- Needs the neuron to depolarise away from its resting potential, which expels a magnesium ion block from its pore.
- Requires both depolarisation and glutamate for it to open its pore.
- Allows calcium into the cell (unlike AMPA).
18
Q
Evidence that LTP depends on the activation of NMDA receptors.
A
Drugs that block the NMDA receptor prevent LTP
induction without affecting baseline responses (eg. AP5, competitive antagonist; MK-801, non-competitive antagonist; 7-chlorokynurenic acid , glycine antagonist).
19
Q
What is a competitive agonist?
A
Drugs that compete with glutamate for the receptor binding site.
20
Q
Evidence that LTP depends on a rise in intracellular calcium.
A
Drugs that interfere the increase of Ca2+ into the post-synaptic cell prevents LTP induction.
21
Q
What happens during LTP induction?
A
- Initiate Ca2+ dependent signalling cascades.
- Activate protein kinases (enzymes that modify existing proteins).
- Initiate transcription/translation of new proteins (Ca2+ turn on genes that leads to new protein synthesis).
22
Q
4 mechanisms of LTP expression
A
- Increased probability of neurotransmitter (glutamate) release.
- Changes to functional characteristics of synaptic AMPARs (more sensitive).
- Insertion of existing AMPARs into the synapse (AMPARs moved into the synapse).
- Increase in the number of AMPARs by protein synthesis (new AMPARs).
23
Q
4 stages of LTP
A
- Post-tetanic potentiation.
- Short-term potentiation.
- Early-LTP.
- Late-LTP.
24
Q
Post-tetanic potentiation
A
- Brief (seconds to minutes).
- Does not require NMDA.
- Caused by temporary increase in presynaptic Ca2+ and increased probability of neurotransmitter
release.
25
Short-term potentiation
1. Minutes to 1 hour.
2. Requires NMDAR and post-synaptic Ca2+ influx.
26
Early-LTP
1. 1 - 5 hours.
2. Requires activation of protein kinase but not protein synthesis.
27
Late-LTP
1. Hours to years.
2. Requires new protein synthesis.
28
Which stages of LTP do protein kinase inhibitors block?
Blocks early-LTP. Does not block PTP or STP.
29
What might happen to AMPA receptors during early-LTP?
Conductivity of existing AMPARs changed by phosphorylation of GluA1
subunit.
Trafficking existing AMPARs from inside the cell to the synapse.
30
What is the main excitatory neurotransmitter in the brain?
Glutamate.
31
Which receptor underlies LTP induction?
NMDA.
32
Which receptor underlies LTP expression?
AMPA
33
Which ion is crucial for LTP induction?
Ca2+
34
Martin et al.'s (2000) 4 criteria to assess LTP as a memory mechanism.
1. Detectability.
2. Anterograde alteration.
3. Retrograde alteration.
4. Mimicry.
35
Detectability criterion
We observe detectable increases in synaptic strength after a memory is formed.
36
Anterograde alteration criterion
If LTP is blocked during learning, no memory is formed. LTP required for storing memories.
37
Retrograde alteration criterion
Disrupting or changing LTP should impair the memory. LTP required for maintaining memories.
38
Mimicry criterion
Artificially inducing LTP to create false memories.
39
Moser et al. (1993) on why there was a confound in early studies of learning and field potential increase
There is a strong linear correlation between field potential changes and brain temperature (eg. exploration, ambient heating, running on treadmill).
40
How to bypass the confound of brain temperature/field potential changes?
Fear conditioning and the amygdala (not confounded by locomotor activity as rats freeze).
41
Rogan et al. (1997) LTP and fear conditioning.
Experimental group froze more to the tone than controls, showing stronger learning. The amplitude of field potential (recorded in amygdala) evoked by the tone was also much larger in the conditioned than control rats.
42
McKernan and Schinnik-Gallagher (1997) dead rat tissue slices.
Stimulated thalamic fibres (auditory thalamus -> lateral amygdala). Recorded threshold for depolarisation in lateral amygdala neurons.
Found a reduced threshold for EPSCs (an excitatory response) in paired group (vs. unpaired/naïve). Response carried by AMPA currents (it still seen even after AP5 blocked NMDARs).
43
Kim and Cho (2017 using Fos-CreER mice
Labelled neurons in amygdala that either responded to CS+ or CS- and investigated the size of EPSC in individual neurons. Only neurons responding to CS+ showed potentiation. (Evidence of LTP-like changes in the brain as a consequence of learning).
44
Whitlock et al. (2006) inhibitory avoidance and LTP in hippocampus (2 results).
Rats trained that the dark side of the box led to shock.
1. Found evidence of hippocampal LTP markers in inhibitory avoidance group (but only transiently elevated).
2. Field potentials amplitudes in IA group had a greater variance. Rather than just an increase in potentiation, some synapses potentiated and some depotentiated.
45
What are 2 markers indicative of LTP?
1. Phosphorylation of AMPA GluR1 subunit.
2. AMPA GluR1/GluR2 expression.
46
Do we have evidence that learning causes LTP-like changes in the amygdala and hippocampus?
1. Yes, for amygdala.
2. Little direct evidence for hippocampus.
47
LTP expression pre-synapse and post-synapse.
Pre-synapse: increased glutamate release.
Post-synapse: increased post-synaptic conductivity via AMPARs.
48
Rats with hippocampal lesion in the watermaze
The sham group spent a larger percentage of time in the target quadrant than the HC lesion group.
49
How to block NMDA receptors to prevent LTP induction?
AP5 competitive NMDA receptor antagonist.
50
Morris et al. (1986) watermaze with AP5 mice
1. AP5 increases latency to find
platform during training.
2. AP5 impairs memory of platform location during transfer test (no preference for platform quadrant).
51
Bannerman et al. (1995) on the effects of pre-training with AP5 mice
Spatial pre-training without AP5 (‘downstairs’) prevents spatial memory deficits
when trained with new spatial cues with AP5 on-board (‘upstairs’). Quadrant preference was not impaired.
Even with pre-training, HC lesion impaired memory but AP5 did not.
52
Pharmacological approach 3 problems
1. Most studies deliver NMDA antagonists into cerebral ventricles (not hippocampal specific).
2. NMDA antagonists cause sensorimotor impairments.
3. NMDA antagonists do not produce watermaze deficits if drug-free pre-training is
given.
53
What are the 4 subunits of NMDAR?
1. 2xNR1.
2. 2xNR2A.
(Alternatively, GluN1 or Grin1).
54
What are the subunits of AMPAR?
GluA1/2/3/4. (Also GluR or Gria).
55
Tsien et al. (1996) CA1-specific knockout of GluN1 subunit (NMDA subunit) in watermaze performance
Profound LTP impairment and no quandrant preference. However, mice were also impaired at finding platform when cued by a large visible landmark (HC lesioned mice don't show this impairment; potentially caused altered cortical function).
56
Bannerman et al. (2012) hippocampal specific GluN1 knockout mice and watermaze task.
Controls had normal LTP in CA1 and CA3.
GluN1 KO mice had normal LTP in CA3 but no LTP in CA1. These mice had normal learning (time) and memory (quadrant) in watermaze.
57
Bannerman et al.'s hypothesis on the function of hippocampal NMDAR
Discriminating between competing memories (disambiguate between possible memories).
58
Bannerman et al. (2012) beacon task with 2 balls that indicate the location of the platform (one is a decoy) and GluN1 KO mice
GluN1 KO mice were impaired if they started near the decoy. They could not inhibit themselves from swimming toward the decoy (dummy beacon). Unimpaired when beacons were visually very different (so task was non-spatial).
Hippocampal NMDARs for resolving ambiguity between competing stimuli.
59
Bannerman et al. (2012) reference memory in radial arm maze and GriN1 KO
GluN1 mice impaired on task. Conflict between intramaze cues and extramaze cues (all arms look the same.
60
Zamanillo et al. (1999) GluA1 KO mice LTP and watermaze performance
Impaired hippocampal LTP. No watermaze impairment in transfer test (preferred quadrant).
61
Watermaze task 2 trials
1. Training trials (learning): test time to learn.
2. Transfer test (memory): remove platform and test quadrant preference.
62
Reisel et al. (2002) on whether GluA1 KO mice had developed a non-hippocampal spatial learning mechanism to compensate
Hippocampal lesions impaired the performance of wildtype and KO mice equally.
63
3 findings about hippocampal LTP and spatial learning/memory in watermaze
1. Hippocampal GluN1 KO and GluA1 KO mice have impaired hippocampal LTP.
2. Hippocampal GluN1 KO and GluA1 KO mice have normal watermaze performance.
3. Hippocampal LTP ≠ spatial learning and memory in the watermaze.
64
What does the T-maze and watermaze test?
Watermaze: spatial reference memory (allocentric representation).
T-maze: spatial working memory (need to learn to alternative between the arms for food - know what they chose last time).
65
GluA1 KO mice performance on T-maze alternation
Impaired performance compared to wildtypes. GluA1 KO mice have impaired spatial WM.
66
Schmitt et al. (2003) spatial reference (never has food) and working memory (remember previous choices) together
Found a dissociation between spatial reference memory and working memory in GluA1 KO mice. Impaired WM.
67
Spatial memory hypothesis of hippocampal LTP
GluA1/GluN1-dependent LTP is not necessary for spatial reference memory in watermaze.
However, it is necessary for spatial WM (flexible, temporally specific information to guide behaviour).
Different forms of synaptic plasticity underlie different forms of spatial learning.
68
Liu et al. (2012) using optogenetics and c-fos activated hippocampal cells
C-fos and opsin: neurons that were active in a specific context could be tagged.
Mice fear conditioned in location B but with the activation of neurons that were active in location A: going back to location A made the mice freeze (not seen in location C).
69
Redondo et al. (2014) using aversive vs. rewarding memory engrams
Tagged neurons that were active during an aversive vs. rewarding experience.
Artificially reactivated those neurons in specific locations of the box.
They showed that the reactivation of the aversive engram led to a place avoidance; the rewarding engram led to a place preference.
70
3 caveats of mimicry experiments
1. Limited behavioural expression of memory (freezing or approach/avoidance). (In real life, not all neurons in the engram would be active during a window of time).
2. Hippocampal lesions do not always impair contextual fear conditioning. Still unclear on the role of HC.
3. The context-shock association may not be encoded/stored within the
hippocampus. So what memory is retrieved?
71
What does hippocampal LTP impair/not impair?
Impairs spatial choice (discriminating between different memories but using spatial memory in some way - retrieval cue evokes more than one memory; decoy beacon).
Does not impair spatial knowledge (watermaze; spatial information encoding) or non-spatial choice (associative learning of beacons).
