Synaptic Plasticity and Memory Flashcards
Describe the taxonomy of memory
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)
What is the EPSP a measure of?
Strength of AMPAR mediated synaptic transmission
What are the 3 forms of synaptic plasticity
LTP
LTD “de novo”
LTP depotentiation
What are the 3 classical properties of LTP that may be relevant to its role in memory?
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
Is associativity relevant to all forms of LTP?
No, but is relevant to NMDAR dependent LTP in hippocampus
NMDAR detect a coincidence of post-synaptic depolarization and pre-synaptic glutamate response
Describe a behavioural impact of associative conditioning?
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
Describe Hebb’s postulate about associative conditioning
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
Is it feasible to make determinations about behaviour based on the cellular change that occurs?
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
What are the criteria for assessing and memory hypothesis?
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
Describe anterograde alteration
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
What are the issues with attempting to show anterograde alteration?
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?
Describe the system for studying spatial memory
Morris Water Maze
Does NMDAR blockade impair spatial memory?
Yes; NMDAR blockade (D,L - AP5) impairs water maze reference in memory formation
LTP was blocked relative to the vehicle treated controls
How can intraventricular drug delivery be improved?
Intrahippocampal drug delivery via catheter
Fairly selective due to hippocampus surrounded by white matter
Describe D-AP5 on the ability of mice to on day learning
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
Describe the role of hippocampal NMDA and AMPAR in the encoding and retrieval of one-place memory
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
Describe the role of GluA2 lacking AMPARs in synaptic plasticity and memory
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
Describe Zhou et al. work on gluA2 lacking AMPARs and LTP
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)
Summarise NMDARs and AMPARs in memory encoding and retrieval
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
Is it possible to saturate LTP physiologically on the extrinsic or intrinsic pathways of the hippocampus?
Easiest pathway to observe is EC - DG (perforant pathway)
Hypothesized that saturation of LTP in the perforant pathway should inhibit hippocampal dependent learning
How can LTP saturation be achieved?
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
What were the results of the LTP saturation in the perforant pathway?
Water Maze; saturation of dentate LTP prevents learning of spatial information
Describe the impact of targeted deletion of NMDA receptors in the CA3 region
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
Is the CA3 required for pattern completion?
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
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
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?
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
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
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
Can PKM-zeta be blocked?
Yes; ZIP
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
What is detectability?
If an animal displays memory of previous experiences, change in synaptic efficacy should be detectable somewhere in the nervous system
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)
Is there an impact of exploration behaviour and brain temperature?
Yes; increasing EPSP slope results in an increase in brain temperature
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
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
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
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)
Describe the learning related changes in the hippocampus
Step-through inhibitory avoidance
Inhibitory avoidance training induces hippocampal LTP. Increase in synaptic strength
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
Describe Arc (IEG)
Expressed when synapses are active
RNA is targeted to active dendritic spines
Describe PSD-95
Expressed in post synaptic density (area with proteins required for synaptic plasticity and signal transduction)
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
Describe c-fos
Only expressed in activated neuronal cells
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
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
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)
