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BMS 248 - Neural circuits > Learning and memory II > Flashcards

Learning and memory II Flashcards

1
Q

What did Donald Hebb propose?

A

That memories start in SYNAPSES:

  • The COORDINATED activity of a presynaptic terminal and a postsynaptic neuron STRENGTHENS the connection between them
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2
Q

Where was Hebb’s hypothesis tested?

Why?

A

In the hippocampus

The hippocampus is involved in memory

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3
Q

What 2 things can change the hippocampus?

A
  • London taxi drivers - bigger hippocampus

- Neurodegenerative diseases attack the hippocampus early

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4
Q

What is the simplified circuit of the hippocampus?

A
  • Input
  • Dentate gyrus
  • CA3
  • CA1
  • Output via fornix and subiculum
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5
Q

What are CA3 cells aka?

A

Mossy fibres

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6
Q

What are the connections between CA3 and CA3 aka?

A

Schaffer collaterals

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7
Q

Which synapase is used to study the mechanisms of LTD and LTP?

A

The synapse between CA3 and CA1 neurons in the HIPPOCAMPUS

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8
Q

What happens when the CA3 is electrically stimulated?

A

There is production of an EPSP in CA1

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9
Q

What happens when the CA3 is electrically stimulated with HIGH FREQUENCY stimulation?

What is this called?

A

There is an increase in the amplitude of EPSPs

This is called long-term potentiation (LTP)

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10
Q

What properties does LTP show?

A

1) Input specificity

2) Co-operativity (co-incidence) which doesn’t require high frequency stimulation

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11
Q

How does LTP show input specificity?

What does this also show?

A

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

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12
Q

How does LTP show co-incidence without HFS?

A
  • Can depolarise both pre- and post- synaptic neurons at the SAME time
  • This will cause the synapse to undergo LTP
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13
Q

What does the mechanism of co-incidence without HFS suggest?

A

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
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14
Q

What are the 2 different ideas about how LTP could occur?

Which one has more evidence?

A

1) By pre-synaptic changes (proteins change number or properties)

2) By a postsynaptic event
- -> More evidence!!

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15
Q

What substance is important in triggering LTP?

How?

A

Ca2+:

Ca2+ though NDMA receptors is activated by the binding of GLUTAMATE, which is released from the presynaptic membrane

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16
Q

What occurs in the NDMA receptors when the cell is hyperpolarised?

A

Mg2+ block in the pore of the channel

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17
Q

What happens when the NDMA receptors are activated with glutamate, when they are blocked with Mg2+?

A

The channels don’t open much

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18
Q

How is the Mg2+ block removed from the NDMA receptor?

How does this trigger LTP?

A

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)

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19
Q

How does subsequent depolarisation of both the pre- and post synaptic neuron cause simultaneous activation?

A

Causes release of glutamate from the presynaptic neuron

AND

Removal of the Mg2+ block from the postsynaptic neuron due depolarisation

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20
Q

How does high frequency stimulation cause LTP?

A
  • 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
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21
Q

What are the differences between EARLY and LATE LTP?

A

Early:

  • No protein synthesis
  • ‘LTP induction’

Late:

  • Protein synthesis
  • ‘Expression of LTP’
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22
Q

How does Ca2+ mediated entry induce early phase LTP?

A

Activates calmodulin kinase II (CaMKII), which phosphorylates other proteins, leading to enhances AMPA currents

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23
Q

Where is CaMKII present?

A

In the post synaptic density

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24
Q

What is the structure of CaMKII?

A

2 different subunits - regulatory and catalytic

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25
Q

Describe the activation of CaKII

A
  • 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
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26
Q

What is the alternative idea about Ca2+ induced LTP, that doesn’t involve the activation of CaMKII?

A

Involves PKC

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27
Q

Why does glutamate current increase with LTP?

A

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)
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28
Q

How long does it take for long-term LTP to occur?

A

1 hour after initiation

29
Q

What is important in long-term LTP?

A

cAMP signalling and CREB

30
Q

What is CREB?

What does it do?

A

A calcium element binding protein

Regulates expression of some genes

31
Q

At rest, what happens to the genes that are controlled by CREB?

What does this cause?

A

They are bound to CREB-2

Results in NO transcription of the genes

32
Q

During LTP, what happens to CREB-2?

What does this cause?

A

CREB-2 is substituted for CREB-1
CREB-1 is then phosphorylated

This increases the transcription of the CREB target gene

33
Q

During LTP, what causes phosphorylates and activates CREB-1?

A

PKA (protein kinase A)

34
Q

What does inhibiting LTP cause?

A

Inhibition of some memory formation

35
Q

What mutations affect different aspects of learning?

A

CaMKII, NMDARs, cAMP pathway

36
Q

What are nootropics?

What are the problems with this statement?

A

Drugs that enhance memory and LTP

No direct evidence but correlative evidence

37
Q

How can we try to understand how memory is encoded in LTP? (experimentally)

A

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)
38
Q

What else is involved in memory?

A

LTD - Long term depression

A related form of synaptic plasticity

39
Q

What is LTD?

A
  • An activity induced, long lasting reduction in synaptic efficacy
  • Decrease in EPSP amplitude
40
Q

Where can LTD occur in the brain?

A

Cerebellum and hippocampus

41
Q

Is LTD the opposite of LTP?

Why?

A

NO

If trigger LTD - doesn’t mean you forget something

42
Q

What are the 2 main types of LTD?

What are the mechansims of each?

A

1) Depotentiation
2) LTD de novo

Mechanisms are pretty much the same for both

43
Q

What is depotentiation?

A

Removal of previous LTP

44
Q

When does LTD de novo occur?

A

When there is no previous potentiation

45
Q

What is Hebbian LTD?

How is this different to non-Hebbian LTD?

A

Hebbian - Involves ONE synapse

Non-Hebbian - doesn’t require presynaptic activity

46
Q

What are the general mechanisms for LTD induction?

A

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
47
Q

What is the circuitry involved in LTD?

A

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
48
Q

In LTD, what happens when the Climbing fibre in the cerebellum is activated?

A

Large depolarisation of the PC

49
Q

How do climbing fibres form connections with PCs?

A

Many synapses on one PCs

50
Q

How do parallel fibres form connections with PCs?

A

One synapses on many PCs

51
Q

What happen when stimulate the parallel fibre and climbing fibre in the cerebellum at the same time?

What is this?

A

See a REDUCTION in the synapse between the PARALLEL FIBRE and the PC

This is LD

52
Q

Is LTD input specific?

53
Q

What is LTD involved in the regulation of?

How?

A

Dexterous manipulations

Synapses carry error messages

54
Q

What receptors are used in cerebellar LTD?

A
  • Metabotropic GluR
  • AMPA R
  • Voltage gates Ca2+ channels

NOT NDMA receptors

55
Q

What is needed for cerebellar LTD?

A

Activation of BOTH the climbing fibre and the parallel fibre

56
Q

What does activation of the climbing fibre cause?

A
  • Release of glutamate
  • Activation of AMPA receptors of the PC
  • Depolarisation of the PC
  • Activation of Ca2+ channels
  • Ca2+ increase in the PC
57
Q

What does activation of the parallel fibre cause?

A
  • Release of glutamate
  • Activation of a metabotropic glutamate receptor and G protein cascade
  • Production of secondary messenger DAG
  • DAG activates PKC
58
Q

What is DAG?

A

Diacylglycerol

59
Q

In the PC, how do the 2 pathways (from CF and PF) converge?

A

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

60
Q

In the purkinje cell, what does PKC do?

A
  • Phosphorylate AMPA receptors at the GluR2 subunit
  • Reduces AMPA receptor numbers by endocytosis
  • Reduces AMPA currents
61
Q

How can the AMPA receptor distinguish between phosphorylation by LTD or LTP mechanisms?

A

Phosphorylate at different subunits on the receptor

62
Q

How is LTD caused in the hippocampus?

A

Stimulation of the CA3/CA1 synapse with LOW frequency stimulation

63
Q

What is hippocampal LTD dependant on?

64
Q

How can LTP and hippocampal LTD both be Ca2+ dependant?

A
  • 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)

65
Q

What does the low concentration of Ca2+ in LTD trigger?

How is this different to the high concentration in LTP?

A

Small increases:

  • Trigger more phosphatase action
  • Reduce AMPAr efficacy

Large increases:

  • Trigger more protein kinase activity
  • Increase AMPAr efficacy
66
Q

How are the processes of LTP and LTD linked?

A

In the hippocampal CA3/CA1 synapses

67
Q

So does LTP + LTD = memory?

68
Q

What changes occur in long-term memory?

A

Distributed, structural changes in the ENTIRE brain (not just individual neurons)

69
Q

What can happen when 2 neurons that are converging on the SAME neuron fire together?

A

STRENGTHENING - One pathway (that was orignally weak) can no activate the neuron when fire on its own

BMS 248 - Neural circuits (16 decks)

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