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Learning & Memory > Lecture 7 - Gene Expression in L & M > Flashcards

Lecture 7 - Gene Expression in L & M Flashcards

1
Q

How can the postsynaptic response change?

A
  • AMPA receptor trafficking and different gating
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2
Q

When is the point when long term synaptic plasticity comes into play and gene expression is needed?

A

2 hours

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3
Q

What kinds of changes can occur for long lasting effects?

A
  • More dendritic spines
  • More synapses
  • Increased glutamate receptor expression
  • Altered electrical properties of membrane
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4
Q

What experiment did Nguyen et al (1994) do?

A
  • Inducing LTP in vitro with high freq tetanus

- Included actinomycin D early and later in LTP

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5
Q

What is actinomycin?

A

An inhibitor of gene expression that binds to DNA

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6
Q

What was Nguyen (1994)’s result?

A

When inhibited gene expression late in LTP there was no effect, however when included early LTP did not occur

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7
Q

What is anisomycin?

A

An inhibitor of protein synthesis

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8
Q

What was shown by Flexner in 1963?

A

Long term but not short term memory impaired by intracerebral inhibitors of protein synthesis (puromycin)

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9
Q

What experiment did Montarolo et al (1986) do?

A
  • Had aplysia sensory and motor neurons in culture
  • Added 5-HT (serotonin) to simulate shock twice 24 hours apart
  • Added 5x the serotonin to others
  • Inhibitors of synthesis were added at different times
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10
Q

What were the results of Monarolo (1986)’s experiment?

A

The cells that were given 5x the serotonin had a much larger response after 24 hours if the inhibitors were added late

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11
Q

What are immediate early genes (IEGs)?

A

mRNA induced within 2 hours without need for protein synthesis

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12
Q

What are regulatory IEGs?

A

encode transcription facotrs that control late response genes

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13
Q

Give 3 examples of regulatory IEGs

A
  • c-fos
  • zif268
  • c-jun
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14
Q

What are 3 examples of effector IEGs and their functions?

A
  • Arc - AMPA trafficking
  • BDNF - growth of synapses and increases response to NT
  • Homer1a - signalling and synaptic homeostasis (connects metabotropic glutamate receptors to IP3 receptors)
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15
Q

What are all IEGs a target of?

A

transcription factor CREB

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16
Q

How does Arc work in LTD and LTP?

A

LTD - Forms a complex with dynamin and endophilin which internalises AMPA receptors
LTP - complexes with Wave3 (actin nucleating protein) which increases dendritic spine growth

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17
Q

What did Bourtchuladze do in 1994 and what were the results?

A
  • Knocking out alpha+delta isoform of CREB in mice gives impaired late phase LTP. (but not very much)
  • Had no effect on PPF (so short term plasticity)
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18
Q

Why did knocking out alpha-CREB not have as much as an effect on LTP than thought?

A

CREB has multiple isoforms so beta-CREB was upregulated

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19
Q

How does CREB activate gene expression?

A

If CREB’s KID domains are phosphorylated 2 CBPs can bind and open DNA up so CREB binds to CRE and activates txn

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20
Q

What is the structure of CREB?

A
  • Basic domain - DNA binding
  • Leucine zipper - for dimerisation
  • Kinase inducible domain (KID) (serine 133) (phosphorylated)
  • 2 glutamine rich transactivation domains
21
Q

What is CBP and what is its function?

A

CREB binding protein.

Has histone acetyl transferase activity to open up DNA to CREB

22
Q

Where and How does CREB get phosphorylated?

A

On serine 133

Ca and cAMP activated kinases phosphorylate it

23
Q

What is mGluR and what does it do?

A

A GPCR on the post synapse.

Can inhibit AC and cAMP

24
Q

What are 3 ways Calcium increases CREB txn?

A
  • Ras - MAPK pathway activates RSK2 which is a CREB kinase
  • Ca in nucleus activates CaMK IV which phoshorylates CREB
  • Ca activates AC
25
Q

Who quietened the contension around CREB?

A

Kida et al (2002)

26
Q

What was Kida et al (2002)’s experiment?

A
  • mutated CREB phosphorylation site to an alanine and fused it to the LBD domain of an estrogen receptor (mutated to bind tamoxaphan instead) that is retained in the cytoplasm in the absence of a ligand (inducible inhibitor)
  • When given TAM the mutated CREB can move to nucleus and inhibit txn
  • Also expression of mutant protein controlled by CaMKII promoter restricting it to CA1 neurons
27
Q

Why did Kida et al make all these changes to CREB?

A

Allowed them to control where and when the mutant CREB was expressed so there was no interference with development

28
Q

What is the SRE and where is it?

A

Serum response element

-310 from IEGs (CRE is -60)

29
Q

How is the SRE activated?

A

Calcium in cytoplasm activates MAP kinases which make 2 SRFs and 1 Elk1 form a complex in nucleus that binds and activates

30
Q

What is the other transcription factor domain that contributes to plasticity-induced genes?

A

SRE

31
Q

What kind of specificity can you get with IEGs?

A

Different numbers of pulse trains give different IEGs

32
Q

What are 4 ways Ca could POSSIBLY qualitatively or quantitatively affect the cells txnal response?

A

magnitude/peak amplitude
duration
spatial properties
source/site of entry

33
Q

How do calcineurin and CaMKinases affect the txnal response with Ca?

A
  • Calcineurin binds Ca with high affinity (Kd 28 pM)
  • CaMKinases at low affinity (Kd 40 nM)
  • > Calcineurin activation requires lower Ca conc than CaMKIV
34
Q

How does calcium go back down to resting levels?

A

Plasma membrane calcium ATPases
Na/Ca exchanger
Pumped back into the ER by SERCA

35
Q

Who showed that nuclear calcium was required for CRE-dependent Ca activated txn?

A

Hardingham et al (1997)

36
Q

What was Hardingham et al (1997)’s experiment?

A

Nuclear microinjection of a non-diffusable (attached to large dextran molecule) calcium chelator (BAPTA) and did immunofluorescence to CRE.
Added Ca and added cAMP in different cells

37
Q

What were the results of Hardingham’s immunofluorescence?

A

Cells with calcium chelator showed low CRE

Only showed high CRE when cAMP added

38
Q

What did Hardingham show?

A

SRE activated by cytosolic Ca was enough to activate expression with out nuclear activation of CRE

39
Q

How did Hardingham’s results translate into neurons?

A
  • With low freq stimuli get low Ca only in cytoplasm so only get SRE activation
  • With high freq stimuli get high Ca so it forces its way into the nucleus activating SRE and CRE
40
Q

How many SREs and CREs does c-fos have?

A

1 SRE, 1 CRE

41
Q

How many SREs and CREs does Zif268 have?

A

4 SREs, 1 CRE

42
Q

How many SREs and CREs does Arc have?

A

1 SRE, 1 CRE, 1 MRE (MEF2 response element)

43
Q

What experiment did Steward et al (1998) do to with dendritic targetting?

A

Took readings of how much Arc mRNA were in differently functioning parts of the dentate gyrus in an activated and non activated (control) region

44
Q

What were Steward’s results?

A

Showed much increased Arc mRNA in the activated region and different levels in different functioning parts.
Showed a 3’ untranslated region of rat mRNA contained dendritic targetting element

45
Q

Who showed that local translation occurred in dendritic targetting and how?

A

Aakalu et al (2001)
Made a GFP reporter flanked by 5’ and 3’ UTR of CAMKII-a (known to target synapses like Arc)
Looked at expression of GFP in response to stimulus.
In response to BDNF and in the presence of inhibitors of txn (showing its local) got more GFP

46
Q

Why can a GFP signal sometimes go down when it actually isn’t?

A

Shining high intensity light and cause photo bleaching

47
Q

What steps could be regulated locally in the growing dendrite?

A
  • RNA trafficking
  • Removal of RISK
  • Assembly of tln complex
48
Q

What is a possible mechanism of tln initiation for dendrite growing?

A

Phosphorylation of eIF4E binding proteins (4E-BPs) by MAP Kinases from Ras pathway

49
Q

How is associativity involved in dendritic growing?

A
  • Weak associative stimuli can only activate local translation
  • The strong stimuli can activate local tln and transcription

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