L12 - LTP Flashcards
What is the Hebbian synapse?
Coordinated activity of presynaptic terminal and a postsynaptic neuron strengthen the synaptic connections between them
How was the idea of the Hebbian synapse tested?
Tested on the hippocampus
- Evidence hippocampus is involved in memory
- Alzheimers hits the hippocampus early
Simplified hippocampal circuits
- Input –> dentate gyrus – performant
- Dentate gyrus –> CA3 – mossy fibred
- CA3 –> CA1 – Schaffer collaterals
- Output via formix and subiculum
What is the most important synapse to study for LTP and LDP?
Synapse between CA3 and CA1 neurons
How is LTP phenomenon tested?
Usually tested using CA3 to CA1 synapses
- Use two different electrodes
- Produces an EPSP
- Activated CA3 cells with high frequency stimulus - produces a long-lasting potentiation
What two characteristics does LTP show?
Input specificity
- Only synapses in input 1 affected not input 2
- Mechanism of LTP is located in synapse not cell bodies
Cooperativity
- Do not need high frequency stimulus of synapse to trigger LTP
- Can depolarise both presynaptic and postsynaptic neurons at the same time
What is associative learning?
Two pathways converging on the same target can both be strengthened if they fire together
- Use both conditioned and unconditioned stimulus
- One pathway may be quite weak
How does LTP occur?
Evidence suggests a post-synaptic event
- Critical role of Ca
Where does the Ca come from in LTP?
Ca comes from the NMDA receptors
- Glutamate released from pre-synaptic cells acts on both AMPA and NMDA receptors in postsynaptic cell
- AMPA receptors – depolarise membrane
- NMDA receptors – depolarise a little (permeable to Ca)
What does Ca trigger in the post synaptic cell?
When Ca enters there are process that lead to an increase in number of AMPA receptors
What may cooperativity be a result of?
NMDA receptor properties
What happens to NMDA receptors when the cell is hyperpolarised?
When cell is hyperpolarised, NMDA receptor is blocked by Mg
- Voltage dependent MG block
- Even if NMDA receptors is activated by glutamate it doesn’t work much
What do NMDA receptors need to be activated fully?
NMDA receptors need to be indirectly pre-activated by a separate depolarising input
Why do you use high frequency stimulation of presynaptic neurons?
Greater depolarisation of postsynaptic membrane
What are the differences between early and late phase LTP?
Early phases - do not require protein synthesis – induction
Late phases – require protein synthesis – expression
NMDA receptor mediates an increase in?
Ca which activates calmodium kinase II
What is the role of CaMKII?
Phosphorylates a large number of other proteins
CaMKII post synaptic density?
2-5%
CaMKII structure?
Multiple catalytic subunits
What does Ca in LTP trigger in CaMKII?
Autophosphorylation and constant activation triggered by Ca in LTP
- Activated by a second messenger – Ca + calmodium
Phosphorylation enhances AMPA currents
What other kinases are involved in LTP?
PKC
Knockout and inhibition studies on PKC function in LTP?
Knockout and inhibition studies conflicting
- Inhibitors
- Not 100% specific
- Mostly activate PKC
- Knockout
- Messes up development
- Affects many other pathways of PKC
How does glutamate increase the response in the neuron during LTP?
May involve AMPAfication
Delivery of ready prepared AMPA receptors to the synapse
After how long does late phase LTP occur?
Takes effect 1 hour after initiation of LTP
What is expressed in late phase LTP?
Various proteins begin to be expressed
Need an activation of cAMP signalling
This involves a CREB protein
- Regulate expression of target genes
CRE elements in resting state?
CRE elements bound to CREB-2 protein
- No transcription
CRE elements in LTP?
CRE element bound to CREB-1 protein
- This protein is phosphorylated allowing gene transcription
- Expression of AMPA receptors upregulated
LTP method overview
- Release of glutamate by postsynaptic cell
- Cell depolarises of postsynaptic membrane
- Ca enters through NMDA receptor
- Leads to activation of two kinases
a. Adenylyl cyclase
b. Ca/calmodium - Ca/calmodium activates CaMKII
- Leads to AMPAfication
a. Also changes in properties of AMPA receptors - Adenylyl cyclase leads to activation of PKA
- This migrates to nucleus and leads to expression of many genes
Inhibiting LTP inhibits?
Some memory formation
What is the experimental evidence showing LTP is linked to memory?
AP5 and Morris water maze – time critical effect
Mice in uncomfortable position and needs to find platform to escape water
If repeated mice memorises the location of the platform
Mutations of CaMKII, NMDARs, cAMP pathway all affect?
Aspects of learning
What are examples of drugs that enhance memory and LTP?
AMPAkines – alzheimers
Why is LTP not sufficient for memory?
Only necessary for some memory formation
LTP is a phenomenon linked to?
LTD which can be a related form of plasticity
How was LTP assessed in zebrafish?
Generating reporters of synaptic plasticity
- How is memory encoded in LTP
Use them to define brain areas in which memory is formed
Understand how memory is encoded in synaptic plasticity
What is the phenomenon?
Actively evoked long lasting reduction in synaptic efficacy
- Decreases in EPSP potential
Examples – cerebellum and hippocampus
What are the two types of LTD?
Depotentiation
- Removal of previous potentiation
LTD de novo
- No previous potentiation
Is LTD Hebbian or non-Hebbian?
LTD may be Hebbian - homosynaptic
LTD may by non-Hebbian - heterosynaptic
- Does not require pre-synaptic activity
What are the general mechanisms for LTD induction?
Often required NMDA receptors
Often evoked by low frequency stimulation
Often requires Ca influx and activation of serine/threonine phosphatases
Often involves glutamate but also diffuse transmitters
- 5HT
- Endocannabinoids
The inputs in cerebellum LTD circuitry are?
Inputs are positive through mossy and climbing fibres
- Climbing fibres form synapses with one cell and forms many synapses with Purkinje cell
- When activated it leads to massive depolarisation of Purkinje cell
- Parallel fibres form weak synapses with many cells but only one with each Purkinje cell
The outputs in cerebellum LTD circuitry are?
Outputs are negative through Purkinje fibres
- Parallel fibres –> Purkinje cells
- Climbing fibres –> Purkinje cells
What evokes LTD?
Paired parallel and climbing fibre input to a single Purkinje cell evokes LTD
- Reduction in synapse between parallel fibre and Purkinje cells
Is LDP input specific?
Yes
What indicates a motor error?
Climbing fibre input indicates a motor error and weakens the parallel fibre – Purkinje cell synapse
Cerebellar LTD mechanisms
Does not involve NMDA receptors Involves - Metabotropic glutamate receptor - AMPA receptor - Voltage activated Ca channels
LTD cerebellar method
- Both climbing fibre and parallel fibres need to be activated
- Climbing fibre releases glutamate
- Activates AMPA receptors
- This leads to depolarisation
- Activation of voltage gated Ca channels
- Increase in Ca concentration in cell membrane
- At same time parallel fibres release glutamate
- Activates a G-protein cascade
- Activates phospholipase C
- Activates of PKC
- PKC also activated by Ca increase so the two pathways converge
- PKC phosphorylates AMPA glutamate 2 receptor subunit
- Reduction in AMPA receptor numbers by endocytosis
- Endocytosis inhibitors prevent LTD
Hippocampal LTD occurs in response to?
LTD occurs at the CA3-CA1 synapse with low frequency stimulus
What is depotentiation?
LTD can reverse a previous LTP
Hippocampal LTD
Synapses active when the rest of the cell isn’t become weakened
Hippocampal LTD is dependent on?
Ca
Hippocampal LTD mechanisms
The degree of NMDA receptor activation dictates probability of inducing LTP or LDP
- Higher activation of NMDA receptors leads to activation of LTP
Involves phosphatase/kinase balance
Small increase in Ca in hippocampal LTD leads to?
More phosphatase action
Reduce AMPA receptor efficacy
Large increase in Ca in hippocampal LTD leads to?
More protein kinase action
Increase AMPA receptor efficacy
Why does LTP+LDP not = memory experiment
Marmosets in enriched environment have more spines on some dendrites
- More neurons in their brains
- More synapses forming
