Synaptic Plasticity and Memory Flashcards

1
Q

Describe the taxonomy of memory

A

Declarative (explicit); semantic and episodic memory (hippocampus, medial temporal lobe)

Implicit memory;
Skills and habits (striatum, motor cortex, cerebellum)
Priming (neocortex)
Basic Associative Learning (emotional; amygdala, skeletal musculature; cerebellum)
Non-associative learning (reflex pathways)

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2
Q

What is the EPSP a measure of?

A

Strength of AMPAR mediated synaptic transmission

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3
Q

What are the 3 forms of synaptic plasticity

A

LTP
LTD “de novo”
LTP depotentiation

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4
Q

What are the 3 classical properties of LTP that may be relevant to its role in memory?

A

Persistence; a single HFS (tetanus) can induce LTP for hours/weeks

Input specificity; when you tetanize a group of afferents, only the tetanized ones are potentiated. Important for memory storage (only want synapses that participate in memory to be potentiated)

Associativity; pair stimulation of a weak input to a strong input; the weak input is potentiated (cells that fire together wire together). Extension to this is cooperativity

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5
Q

Is associativity relevant to all forms of LTP?

A

No, but is relevant to NMDAR dependent LTP in hippocampus

NMDAR detect a coincidence of post-synaptic depolarization and pre-synaptic glutamate response

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6
Q

Describe a behavioural impact of associative conditioning?

A

Classical conditioning;

Neutral stimulus (bell) rang = conditioned stimulus 
Unconditioned stimulus such as food = salivation 

When bell and food given at the same time there is an unconditioned response of salivation due to presentation of food
After this training; when a bell is rung, there is salivation as a conditioned response

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7
Q

Describe Hebb’s postulate about associative conditioning

A

When an axon of cell A is near enough to excite a cell B and repeatedly or persistently take part in firing, some growth process or metabolic change takes place in one or both cells such that A’s efficacy as one of the cells firing B, is increased

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8
Q

Is it feasible to make determinations about behaviour based on the cellular change that occurs?

A

No; the role of synaptic plasticity in a particular form of memory is determined by the neural circuit which is implicated

E.g.; a reflex network vs a distributed associative network

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9
Q

What are the criteria for assessing and memory hypothesis?

A

Anterograde alteration; blocking changes in synaptic strength should block memory formation

Retrograde alteration; changing of synapses after the learning task should wipe out the memory that is stored

Detectability; if synaptic changes happen during learning they should be detectable

Mimicry; selective changes in the brain can engineer memories for something that didn’t actually happen

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10
Q

Describe anterograde alteration

A

Interventions that prevent or limit the induction of synaptic weight change during a learning experience should block or impair the animals memory of that experience.

Interventions enhancing plasticity might also improve learning

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11
Q

What are the issues with attempting to show anterograde alteration?

A

What physiological, pharma or molecular genetic manipulations to use? Side-effects?
How to ensure appropriate regional specificity of the treatment for the type of learning/ memory under investigation
Inducibility and reversibility of the treatment?

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12
Q

Describe the system for studying spatial memory

A

Morris Water Maze

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13
Q

Does NMDAR blockade impair spatial memory?

A

Yes; NMDAR blockade (D,L - AP5) impairs water maze reference in memory formation

LTP was blocked relative to the vehicle treated controls

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14
Q

How can intraventricular drug delivery be improved?

A

Intrahippocampal drug delivery via catheter

Fairly selective due to hippocampus surrounded by white matter

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15
Q

Describe D-AP5 on the ability of mice to on day learning

A

Delay-dependent impairment in a delayed matching-to-place task
Only long term memory affected (short term memory was normal)
NMDA receptor activation is required to form a long term memory

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16
Q

Describe the role of hippocampal NMDA and AMPAR in the encoding and retrieval of one-place memory

A

NMDA antagonist; AP5
Blocking NMDA hippocampal receptors for encoding completely blocked the correct exploration
However, AP5 injected before retrieval had no problems with retrieval of memory

AMPAR antagonist (CNQX);

Blockade of AMPARs before retrieval drastically reduced the correct exploration (retrieval of memory)
This links to the fact that AMPARs mediate fast synaptic transmission - functional lesion. Memory can no longer be expressed

NMDA receptors are not required for retrieval of memory, however they are required to encode memories

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17
Q

Describe the role of GluA2 lacking AMPARs in synaptic plasticity and memory

A

GluA2 lacking subunits are permeable to calcium
LTP inducing

LTP induction selectively involved the insertion of GluA2 lacking AMPARs in post-synaptic membrane

This trafficking depends on C-terminal region of GluA1 regions

C-tail of GluA2 is crucial for removal of Glu2 from synapse = LTD

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18
Q

Describe Zhou et al. work on gluA2 lacking AMPARs and LTP

A

Necessary for Ca1 LTP

Genetically modified GluA1 receptors to contain the gluA2 C-tail.
This led to a complete block of LTP
Without this GluA1 C tail; there is a reduction in AMPAR trafficking to post-synaptic membrane

Furthermore, impact on behaviour; necessary for spatial memory formation (Morris Water Maze)

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19
Q

Summarise NMDARs and AMPARs in memory encoding and retrieval

A

For place memory, hippocampal NMDAR activation with the subsequent upreg of GluA2 lacking AMPARs is necessary for the encoding of memory

Further NMDAR activation is NOT required for memory retrieval.

Pharma blockade of AMPARs with CNQX prevents successful memory retrieval

20
Q

Is it possible to saturate LTP physiologically on the extrinsic or intrinsic pathways of the hippocampus?

A

Easiest pathway to observe is EC - DG (perforant pathway)

Hypothesized that saturation of LTP in the perforant pathway should inhibit hippocampal dependent learning

21
Q

How can LTP saturation be achieved?

A

High frequency stimulation across the fibre bundle using bipolar electrodes with a collar and tip (cross bundle tetanisation)

Attempt to potentiate as many inputs as possible

3rd electrode in central of perforant path to induce LTP et end of task to determine if saturation was effective

22
Q

What were the results of the LTP saturation in the perforant pathway?

A

Water Maze; saturation of dentate LTP prevents learning of spatial information

23
Q

Describe the impact of targeted deletion of NMDA receptors in the CA3 region

A

Mice with a targeted deletion of NMDA receptors in CA3 trained in watermaze reference memory task

Retention was normal with all cues present, but impaired when there was only a limited set of cues available

Place cells were more diffuse in CA1 with a limited set of cues, but normal with a full set

24
Q

Is the CA3 required for pattern completion?

A

NMDAR plasticity at CA3 recurrent synapses is necessary for encoding to occur in such a way that pattern completion can occur with partial information

Reactivation of previously strengthened recurrent connections is unnecessary for recall under full-cue conditions

25
What is meant by retrograde alteraion?
Interventions that alter the spatial distribution of synaptic weights induced by prior learning should alter the animal's memory of that experience
26
What are the issues with demonstration of retrograde alteration?
What physiological, pharma or molecular genetic manipulations should be used? What are the side effects/ How can you ensure that the appropriate regional specificity of the treatment is relevant to the type of learning/ memory under investigation How soon after the prior learning experience should the animals be manipulated?
27
How can existing memory traces be disrupted?
LTP induction After LTP induction, a normal sparse pattern of learning-induced potentiation (A) is unreadable against a background of artificial synaptic changes induced after training that contain no meaningful information
28
Describe a trial that demonstrates the disruption of memory via LTP induction
Brun et al Trained in water maze HFS given with a saline vehicle = significant reduction in time spent in correct one of water maze HFS given with CPP (NMDAR antagonist) = no reduction in time spent in the correct zone of the water maze; spatial memory not impacted LFS with CPP or sal; no impact on retrieval/ retrograde memory
29
Describe PKM-zeta
Isoform of PKC; lacks the regulatory component, only has catalytic component Constitutively active Involved with continuous trafficking of AMPARs to result in a long lasting increase in synaptic strength
30
Can PKM-zeta be blocked?
Yes; ZIP
31
What is the effect of ZIP on LTP?
ZIP (PKM-zeta inhibitor) after LTP with completely reverse LTP back to baseline levels However, ZIP doesn't impact the baseline ZIP "erases" spatial memory Therefore, reversal of LTP acts to erase memory
32
What is detectability?
If an animal displays memory of previous experiences, change in synaptic efficacy should be detectable somewhere in the nervous system
33
What are the issues with dectability?
Where should you look in the brain (memory storage) How big a change is expected (storage capacity) Will induction preclude further induction? (saturation)
34
Is there an impact of exploration behaviour and brain temperature?
Yes; increasing EPSP slope results in an increase in brain temperature
35
How can the role of the amygdala in memory be studied?
Fear conditioning Behavioural LTP induced by fear conditioning Behavioural LTP is induced in the lateral nucleus of the amygdala by pavlovlan fear conditioning. Auditory fear conditioning does result in an increase in synaptic strength
36
Does fear conditioning change AMPAR expression?
Similar to LTP; AMPAR is added to post-synaptic membrane during fear conditioning Virus mediated overexpression of GFP tagged GluA1 AMPARs in lateral amygdala Subunits from homomeric receptors containing only GluA1 subunits Most normal AMPARs contain a mixture of subunits, including both GluA2 GluA2 containing receptors pass ionic currents almost equally well in both directions (i.e. at -60mV and +40 mV) Homomeric GluA1 receptors pass much less current in the outward direction (greater rectification). This does not affect normal physiological function, but provides a marker for AMPA insertion Fear conditioning, similar to LTP, results in an increased rectification, indicating that new synaptic AMPARs are inserted during memory formation
37
Does skill learning have an impact on plasticity?
Skill learning causes an increase in evoked responses (EPSP) recorded in the motor cortex (CI) This was a contralateral effect Skill learning results in a partial occlusion of LTP and a facilitation of LTD. Skill learning shifts LTP induction upwards The thing we don't know; is how this information is stored or retrieved
38
Describe behavioural familiarity to a visual stimulus
The more the animal is familiar to the visual stimulus, the less it moves Visual recognition memory formation causes synaptic changes - visual evoked response grows with increased stimulus with a decrease in movement (acquired visual recognition memory)
39
Describe the learning related changes in the hippocampus
Step-through inhibitory avoidance Inhibitory avoidance training induces hippocampal LTP. Increase in synaptic strength
40
Describe a study that combines detectability and retrograde alteration
Development of an optoprobe to label dendritic spines enlarged after motor learning Mice trained to walk on a rotarod without falling off. This training induced dendritic spine enlargement and de novo spine formation - increased in fEPSP in motor cortex after learning Photoactivation of optoprobe to shrink spines (PaRac1) resulted in the loss of memory of the recently learned motor task
41
Describe Arc (IEG)
Expressed when synapses are active | RNA is targeted to active dendritic spines
42
Describe PSD-95
Expressed in post synaptic density (area with proteins required for synaptic plasticity and signal transduction)
43
How are the inputs form the auditory cortex to amygdala organised?
Tonotopically; organised by sound frequency Sound of one frequency will activate a set of synapses Different frequency will activate a different set of synapses
44
Describe c-fos
Only expressed in activated neuronal cells
45
Describe the study that demonstrated synapse-specific encoding and erasure of fear memory in the amygdala
Knock in mice in which Cre is driven by c-fos expression (i.e. only active cells) Injected with a Cre-dependent adenovirus construct that drives yellow fluorescent protein (YFP) expression; labels active inputs during fear conditioning (CS+ or CS-) Replacement of YFP with ChR2 construct enables active afferents to be stimulated ex vivo by blue light Ex vivo stim of CS+ but not CS- elicits larger AMPA/NMAR EPSC ratio in mice trained to assoc CS+ with foot-shock relative to untrained controls LFS depotentiation optogenetic stim of CS+ axons reduced the CS elicited freezing - i.e. reversed the fear memory
46
Describe mimicry
If it is possible to induce an appropriate spatial pattern of synaptic weight changes, the animal should display apparent memory for some past experience which did not occur in practice Formation of artificial memories
47
Is it easier to achieve mimicry in some circuits in comparison with others?
Easier in reflex network leading to a straightforward change in behaviour - e.g. amygdala for fear conditioning More difficult in distributed associative network (e.g. CA3)