Learning and memory II Flashcards
What did Donald Hebb propose?
That memories start in SYNAPSES:
- The COORDINATED activity of a presynaptic terminal and a postsynaptic neuron STRENGTHENS the connection between them
Where was Hebb’s hypothesis tested?
Why?
In the hippocampus
The hippocampus is involved in memory
What 2 things can change the hippocampus?
- London taxi drivers - bigger hippocampus
- Neurodegenerative diseases attack the hippocampus early
What is the simplified circuit of the hippocampus?
- Input
- Dentate gyrus
- CA3
- CA1
- Output via fornix and subiculum
What are CA3 cells aka?
Mossy fibres
What are the connections between CA3 and CA3 aka?
Schaffer collaterals
Which synapase is used to study the mechanisms of LTD and LTP?
The synapse between CA3 and CA1 neurons in the HIPPOCAMPUS
What happens when the CA3 is electrically stimulated?
There is production of an EPSP in CA1
What happens when the CA3 is electrically stimulated with HIGH FREQUENCY stimulation?
What is this called?
There is an increase in the amplitude of EPSPs
This is called long-term potentiation (LTP)
What properties does LTP show?
1) Input specificity
2) Co-operativity (co-incidence) which doesn’t require high frequency stimulation
How does LTP show input specificity?
What does this also show?
Neuron with 2 inputs from different neurons will only increase in EPSP amplitude in synapse 1 if ONLY stimulate synapse 1 with HFS
Synapse 2 is unaffected
Shows the mechanism of LTP to be confined to the synapses and NOT the cell bodies
How does LTP show co-incidence without HFS?
- Can depolarise both pre- and post- synaptic neurons at the SAME time
- This will cause the synapse to undergo LTP
What does the mechanism of co-incidence without HFS suggest?
A mechanism of associative learning:
- One pathway is the unconditioned stimulus (CA3)
- CA3 synapses on CA1
- CA1 regulates response (conditioned stimulus)
- If activate both neurons at the same time (US and CS) –> strengthen the synapse
- Can then use the conditioned stimulus to evoke the response
- CA1 can trigger response without CA3
What are the 2 different ideas about how LTP could occur?
Which one has more evidence?
1) By pre-synaptic changes (proteins change number or properties)
2) By a postsynaptic event
- -> More evidence!!
What substance is important in triggering LTP?
How?
Ca2+:
Ca2+ though NDMA receptors is activated by the binding of GLUTAMATE, which is released from the presynaptic membrane
What occurs in the NDMA receptors when the cell is hyperpolarised?
Mg2+ block in the pore of the channel
What happens when the NDMA receptors are activated with glutamate, when they are blocked with Mg2+?
The channels don’t open much
How is the Mg2+ block removed from the NDMA receptor?
How does this trigger LTP?
When activating the NDMA receptor with glutamate AT THE SAME TIME AS depolarising the membrane
Triggers LTP as as Ca2+ can enter through the NDMA receptor
Ca2+ is the key trigger of LTP (by increasing the number of AMPA receptors in the presynaptic membrane)
How does subsequent depolarisation of both the pre- and post synaptic neuron cause simultaneous activation?
Causes release of glutamate from the presynaptic neuron
AND
Removal of the Mg2+ block from the postsynaptic neuron due depolarisation
How does high frequency stimulation cause LTP?
- Depolarises the membrane of the postsynaptic neuron much stronger due to SUMMATION of EPSPs
- Reach depolarisation threshold this is sufficient enough to remove the Mg2+ block
What are the differences between EARLY and LATE LTP?
Early:
- No protein synthesis
- ‘LTP induction’
Late:
- Protein synthesis
- ‘Expression of LTP’
How does Ca2+ mediated entry induce early phase LTP?
Activates calmodulin kinase II (CaMKII), which phosphorylates other proteins, leading to enhances AMPA currents
Where is CaMKII present?
In the post synaptic density
What is the structure of CaMKII?
2 different subunits - regulatory and catalytic
Describe the activation of CaKII
- Ca2+ bound with calmodulin causes a conformational change in CaMKII (to an open confirmation)
- CaMKII then autophosphorylates itself, leading to the stabilisation of the open confirmation, which can then go on to bind other proteins
What is the alternative idea about Ca2+ induced LTP, that doesn’t involve the activation of CaMKII?
Involves PKC
Why does glutamate current increase with LTP?
AMPAfication:
- Delivery of ready-prepared AMPA receptors to the synapse during LTP
- Increase in AMPA receptors
- Open probabilities of the AMPA receptors increase (more active)
How long does it take for long-term LTP to occur?
1 hour after initiation
What is important in long-term LTP?
cAMP signalling and CREB
What is CREB?
What does it do?
A calcium element binding protein
Regulates expression of some genes
At rest, what happens to the genes that are controlled by CREB?
What does this cause?
They are bound to CREB-2
Results in NO transcription of the genes
During LTP, what happens to CREB-2?
What does this cause?
CREB-2 is substituted for CREB-1
CREB-1 is then phosphorylated
This increases the transcription of the CREB target gene
During LTP, what causes phosphorylates and activates CREB-1?
PKA (protein kinase A)
What does inhibiting LTP cause?
Inhibition of some memory formation
What mutations affect different aspects of learning?
CaMKII, NMDARs, cAMP pathway
What are nootropics?
What are the problems with this statement?
Drugs that enhance memory and LTP
No direct evidence but correlative evidence
How can we try to understand how memory is encoded in LTP? (experimentally)
Generate reporters of synaptic plasticity in zebrafish, in areas of the brain where memory has formed:
- Use pH dependant form of GFP
- Reports the trafficking of AMPA receptors (increases of AMPAr in postsynaptic membrane - increase fluorescence of synapses)
What else is involved in memory?
LTD - Long term depression
A related form of synaptic plasticity
What is LTD?
- An activity induced, long lasting reduction in synaptic efficacy
- Decrease in EPSP amplitude
Where can LTD occur in the brain?
Cerebellum and hippocampus
Is LTD the opposite of LTP?
Why?
NO
If trigger LTD - doesn’t mean you forget something
What are the 2 main types of LTD?
What are the mechansims of each?
1) Depotentiation
2) LTD de novo
Mechanisms are pretty much the same for both
What is depotentiation?
Removal of previous LTP
When does LTD de novo occur?
When there is no previous potentiation
What is Hebbian LTD?
How is this different to non-Hebbian LTD?
Hebbian - Involves ONE synapse
Non-Hebbian - doesn’t require presynaptic activity
What are the general mechanisms for LTD induction?
Many different mechanisms:
- Often requires NDMA receptors but not always
- Often requires Ca2+ influx and activation of serine/threonine phosphatases, but not always
- Often involves glutamate, but can involved other neurotransmitters (eg. 5-HT, Endocannabinoids)
- Often stimulates by LOW FREQUENCY stimulation, but not always
What is the circuitry involved in LTD?
2 inputs into the cerebellum:
- Mossy fibres to granule cells (which form PARALLEL fibres)
- Climbing fibres
- CF synapse with one purkinjie fibre but with MANY synapses
- Parallel fibre forms WEAK synapses with MANY PC but ONE synapse with each PC
In LTD, what happens when the Climbing fibre in the cerebellum is activated?
Large depolarisation of the PC
How do climbing fibres form connections with PCs?
Many synapses on one PCs
How do parallel fibres form connections with PCs?
One synapses on many PCs
What happen when stimulate the parallel fibre and climbing fibre in the cerebellum at the same time?
What is this?
See a REDUCTION in the synapse between the PARALLEL FIBRE and the PC
This is LD
Is LTD input specific?
Yes
What is LTD involved in the regulation of?
How?
Dexterous manipulations
Synapses carry error messages
What receptors are used in cerebellar LTD?
- Metabotropic GluR
- AMPA R
- Voltage gates Ca2+ channels
NOT NDMA receptors
What is needed for cerebellar LTD?
Activation of BOTH the climbing fibre and the parallel fibre
What does activation of the climbing fibre cause?
- Release of glutamate
- Activation of AMPA receptors of the PC
- Depolarisation of the PC
- Activation of Ca2+ channels
- Ca2+ increase in the PC
What does activation of the parallel fibre cause?
- Release of glutamate
- Activation of a metabotropic glutamate receptor and G protein cascade
- Production of secondary messenger DAG
- DAG activates PKC
What is DAG?
Diacylglycerol
In the PC, how do the 2 pathways (from CF and PF) converge?
At the level of PKC:
- PKC is activated by both the influx of Ca2+ though AMPA receptors (activated by CF) AND by DAG, which is activated though PF
In the purkinje cell, what does PKC do?
- Phosphorylate AMPA receptors at the GluR2 subunit
- Reduces AMPA receptor numbers by endocytosis
- Reduces AMPA currents
How can the AMPA receptor distinguish between phosphorylation by LTD or LTP mechanisms?
Phosphorylate at different subunits on the receptor
How is LTD caused in the hippocampus?
Stimulation of the CA3/CA1 synapse with LOW frequency stimulation
What is hippocampal LTD dependant on?
Ca2+
How can LTP and hippocampal LTD both be Ca2+ dependant?
- Degree of NDMA receptor activation is different
- This dictates the probability of inducing LTP of LTD
(In LTD, NDMA receptors are activated much less and the Ca2+ concentration is smaller)
What does the low concentration of Ca2+ in LTD trigger?
How is this different to the high concentration in LTP?
Small increases:
- Trigger more phosphatase action
- Reduce AMPAr efficacy
Large increases:
- Trigger more protein kinase activity
- Increase AMPAr efficacy
How are the processes of LTP and LTD linked?
In the hippocampal CA3/CA1 synapses
So does LTP + LTD = memory?
No
What changes occur in long-term memory?
Distributed, structural changes in the ENTIRE brain (not just individual neurons)
What can happen when 2 neurons that are converging on the SAME neuron fire together?
STRENGTHENING - One pathway (that was orignally weak) can no activate the neuron when fire on its own
