L17 & 18 - Synaptic Plasticity & Associative Learning Flashcards
1
Q
What are cellular mechanisms of learning?
A
- Learned changes in behaviour must correspond to neural changes
- Cajal → “Plasticity” (changes) in synaptic connections responsible for learning and memory - at the time there was a debate whether synapses exist - can shine electrons through and shows theres a space
- Konorski & Hebb both describe models of synaptic plasticity
2
Q
What is the Hebbian synapse?
A
- Biologically significant events (USs) have hard-wired connections controlling behaviour
- e.g. neurons coding for food can directly excite neurons producing salivation
- Neurons for other events (e.g. CSs) form weak (ineffective) synapses with neurons controlling that behaviour - they can become stronger
- Pavlov = These connections must be acquired through learning (between CS and output)
- Hebb & Konorski = These “latent” connections must be strengthened through learning - intially existed but were just to weak to be used/drive input
- Synaptic connection between CS and behavioural output is strengthened when weak CS input arrive simultaneously with strong US input
- “neurons that fire together wire together”
3
Q
What is the evidence of synaptic plasticity in the hippocampus?
A
- Hippocampus proper is comprised of three regions
- CA1, CA2 and CA3
- CA (cornu ammonis)
- CA1, CA2 and CA3
- Synaptic connections in hippocampus
- Very hard to stimulate one fibre and measure from a single neuron
- But organisation of neural circuitry in hippocampus conveniently segregates inputs and throughput
- Perforant path forms synapses with granule cells
- Can implant electrode into perforant path and know it is a cell recording from granule cell
- Can stimulate and record from different locations and know you are measuring a single synapse
4
Q
What is long-term potentiation (LTP)?
A
- LTP is a physiological example of synaptic plasticity
- Potential as a model for neural mechanisms of learning
- Most demonstrations of LTP have been in the hippocampus (in vitro but also in vivo) but also other areas of the brain (e.g. spinal cord)
- Most studies done in vitro
5
Q
What are the steps of demonstrating long-term potentiation? Name only
A
Step 0 - Demonstrating intial effectiveness
Step 1 - Apply higher stimulation
Step 2 - Return to weak stimulation but see grerater response than intial weak response
6
Q
What is step 0 of LTP?
A
Demonstrating intial effectiveness:
- Weak stimulation of Presynaptic input (eg, perforant path to hippocampus) causes little or no activity in post-synaptic neurons (eg, in dendate gyrus (DG) of hippocampus)
- Electrode in performant path
- Worked out level of stimulation that had small output effect on dentate gyrus cells to establish baseline
7
Q
What is step 1 of LTP?
A
Apply higher stimulation:
Strong, high-frequency (eg 100Hz) stimulation of pre-synaptic input causes long-lasting increase in sensitivity of post-synaptic neurons.
8
Q
What is step 2 of LTP?
A
Return to weak stimulation but see greater response than initial weak response:
- Weak stimulation of the pre-synaptic input now produces action potentials in the post-synaptic cells
- Seeing potentiation of synapse rather than fatigue is quite substantial
9
Q
What evidence is there to support LTP?
A
- Measured synaptic efficacy in dentate gyrus in both hemispheres
- After each application of high frequency stimulation (HFS) they increase potentiation in the synapse
10
Q
How is LTP “dose dependent”?
A
- Weak high-frequency stimulation (HFS) can produce short-lived potentiation (10 min), but long-lasting potentiation (hours) achieved by strong HFS
- Activity at synapse produces lasting changes
- HFS often as continuous volley, but can be patterned as bursts at theta frequency (“Theta Burst Stimulation”, TBS): eg, short bursts of 5 pulses in 50ms, repeated every 200ms.
- Hippocampus is naturally active at theta frequency
- Duration of LTP depends on the number of TBSs (theta bursts)
11
Q
What does plasticity look like in long-term depression?
A
- Plasticity is bi-directional:
- You can depress a synapse
- Low-frequency stimulation can reduce synaptic efficacy (LTD)
- Dudek & Bear (1992) - potentiation or depression only occurs at HFS it doesn’t matter what frequency
- Not sure if it is a method for inhibitory learning
12
Q
What are the three properties of LTP that show it as a model of learning and memory?
A
- Persistence: Potentiation is enduring, sometimes lasting weeks.
- Synaptic specificity: Only stimulated pre-synaptic inputs show potentiation ie. no increased sensitivity to other pre-synaptic inputs.
- Within perforant path, different inputs - you can get potentiation in one part and not the other
- Associativity is an exception to synaptic specificity
-
- Associativity….
- Can get LTP at pre-synaptic inputs weakly stimulated at the same time as strong stimulation to separate (but converging on the same neuron) input in certain conditions
- This property most resembles Hebb’s model for how associations are acquired by nervous system.
- Subsequently can later generate behavioural response by themselves
13
Q
Do LTP and learning share a common mechanism?
A
- Correlations between LTP and learning
- Age-related decline in learning correlates with age-related decline in induction of LTP in hippocampus.
- Similar correlations between LTP and learning in mouse model of Alzheimer’s Disease.
- Is learning affected by saturation of LTP?
- Correlations between LTP and learning
- Age-related decline in learning correlates with age-related decline in induction of LTP in hippocampus.
- Similar correlations between LTP and learning in mouse model of Alzheimer’s Disease.
- Correlations between LTP and learning
14
Q
Do learning and LTP share common neurochemistry?
A
- Pharmacological interventions that prevent LTP (block NMDA receptors - key receptor LTP and plasticity) also disrupt learning.
- Conditioned Taste Aversion;
- Conditioned Fear;
- Conditioned Eyeblink;
- Maze learning
15
Q
Synapses
What is the neurochemical basis of LTP?
A
- LTP dependent on release of excitatory neurotransmitter glutamate
- Two types of receptors that have different roles in potentiation
- Glutamate binding to AMPA receptors
- Glutamate binding to NMDA receptors
16
Q
How is the NMDA receptor also involved in LTP?
A
- Glu must also bind to NMDA receptors, opening Ca++ channels
- They trigger other changes in post synaptic neuron that leads to potentiation
17
Q
How is the AMPA receptor involved in LTP?
A
- Glu from pre-synaptic terminal binds to AMPA receptors on post-synaptic neuron, causes immediate excitation (depolarisation) of post-synaptic neuron
- e.g. if stimulate axons strongly, stimulating a large release of glutamate
- When glutamate binds to AMPA it immediately depolarises the post synaptic neuron. Causes shape to change and allows Na+ in
- Fast excitatory post synaptic potentials (EPSPs)
18
Q
What is the process of LTP involving both NMDA and AMPA receptors?
A
- Allowing Ca++ ions into postsynaptic neuron, creates intracellular cascade which increases the number of AMPA receptors = increased sodium influx which depolarises and increases the sensitivity to glutamate
- So ultimately LTP comes about due to increased number of AMPA receptors
19
Q
What special properties does the NMDA receptor have?
A
- NMDA receptors have 2 special properties that underlie synaptic plasticity:
- Admit Ca++ into the neuron (increase AMPA)
- Ca++ channels on NMDA receptors need both at the same time … to be opened :
- ligand-gated – Glutamate (ligand) - so binds onto NDMA receptor and changes shape
- voltage-gated – post-synaptic neuron must be depolarised (this removed magnesium ion which opens calcium channel)
21
Q
What happens when inducing regular LTP from a weak stimulation?
A
Glutamate might bind to NMDA but don’t have enough to bind to AMPA receptors and depolarise the membrane (so calcium ion channel won’t open so no potentiation)
If weak stimulation given at the same time as strong high-frequency stimulation:
- On it’s own weak stimulation won’t depolarise the membrane
- But if giving strong stimulating information to the neuron from a converging synapse to induce action potential, then it will spread along to both synapses so that receptors facing weak stimulating neuron will also be activated (as long as there is some amount of glutamate)
- The aid of depolarisation from the strong high-frequency stimulation site removes the magnesium for the other AMPA receptors facing the weak synapse and since there is a small amount of glutamate to bind it reaches both conditions
23
Q
What is the generating the synaptic change (intial memory trace creation) of LTP?
A
- Rapid “post-translational” changes because they use existing proteins in the neuron & do not require synthesis of new proteins (requires translation from mRNA which is transcribed from the DNA)
- Transient (they revert back to previous state) unless other intracellular processes are activated to stabilise changes (so can lose LTP)
- May explain why recent memory traces can be disrupted by head trauma (concussion causes amnesia for events that occurred a few minutes before an accident.) - so memory changes don’t get consolidated into anything more lasting
- The immediate post-translational change:
- Dendritic spine = Outgrowth of the dendrite from the synapse
- Receptors are not fixed - they sit in the membrane and then drift out of the synapse along the spine and eventually the membrane snaps off into an endosome, carrying the receptor, and is taken back to the synapse (constitutive trafficking)
- This means there is a reserve of receptors at any time
- Once calcium ions enter, they activate protein kinases which leads to greater trafficking (can lead to more glutamate)
- This increases the availability of AMPA receptors and LTP
Ca++ influx triggers enzymes to disassemble actin filaments that otherwise obstruct AMPA trafficking to PSD
24
Q
What is the stablising stage of converting LTP?
A
- Other structures, such as the cytoskeleton, need to be broken down and rebuilt to allow the trafficking to occur. Other enzymes chop through the filament bridges and then enzymes reconstruct the cytoskeleton in a way most beneficial for trafficking.
- It can’t be sustained for a long period of time, need new AMPA receptors
- ## Ca++-dependent cell adhesion molecules (neural cadherins) form bridge between pre and post-synaptic membranes which makes the synapse more stable
- Cadherins make sure they are in line, they have some cohesive force (single-stranded). They are sensitive to calcium
- Ca ++ influx through NMDA-R converts weakly-adhesive monomer to strongly adhesive dimer, stabilising synapse
25
Q
What is the consolidating changes of converting LTP stage?
A
- Weak HFS can produce short-lived potentiation (10 min), but long-lasting potentiation (hours) achieved by strong HFS, or HFS at theta burst frequency.
- This LTP requires translational processes (protein synthesis); drugs that block protein synthesis can prevent long-lasting synaptic potentiation after strong HFS (but have no effect on the initial short-lived potentiation).
****Step 1:****
- Dendritic spines contain machinery for local synthesis of proteins to make AMPA receptors:
- Enduring LTP can be induced in CA1 dendrites that have been dissected away from cell body (soma) that contains nucleus
Step 2:
- New mRNA must be transcribed from DNA in nucleus to supplement mRNA in dendrites.
- Ca++ trigger processes that engage mRNA transcription in nucleus.
- Largely due to Ca ++ entering through voltage-dependent Ca ++ channels at soma, triggered by action potentials passing from dendrites to axon, so transports mRNA back to dendritic spine
- New receptors (Voltage-dependent Ca++ channels) that are like NDMA receptors as they have calcium channel but differ as don’t have binding site on them
- This allows us to have more AMPA receptors available in the synapse, need to grow dendritic synapse to allow new receptors and LTP
- Depends on brain-derived neurotrophic factor (BDNF) and transcription of mRNA.
- New cytoskeleton provides scaffold for routine trafficking of extra AMPA-Rs
- Enlarged spine more effective and more stable. May even lose plasticity. (Small spines learn; large ones remember)
- Longer it is, increase SA, more sensitive it is
- Sustained synaptic activity leads to long-lasting polymerization of actin cytoskeleton = enlarged dendritic spine
26
Q
What is the maintaining changes stage (preventing forgetting) of LTP?
A
- Change in make-up of AMPA receptor:
- Initially, AMPA receptors containing GluA1 subunit (there are four possible subunits of AMPA receptor)
- Long-term up-regulation of synapse involves replacing GluA1 with GluA2 subunit in AMPA receptors (captured from the extra-synaptic pool)
- GluA2 doesn’t support further potentiation
- A new type of PK that is self-activating (lacks inhibitory unit that turns it off) so doesn’t require calcium to turn it on
27
Q
What is the general overview of the LTP process?
A
