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BS42018- Mapping Memories in the Brain > BS42018 L5+6 > Flashcards

BS42018 L5+6 Flashcards

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1
Q

what are two endocrine hormones that markedly influence hippocampal synaptic plasticity?

A

leptin and insulin

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2
Q

where is leptin made and secreted?

A

white adipose tissue (white fat cells in periphery)

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3
Q

what does leptin do?

A

It regulates food intake and body weight and so therefore regulates energy homeostasis via its actions in the hypothalamus.

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4
Q

how does leptin work?

A

by binding to the leptin receptor which is a product of the diabetes (db) gene

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5
Q

how many splice variants does leptin have?

A

6- Ob-Ra: Ob-Rf

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6
Q

describe leptin receptor signal transduction (6)

A
  • Leptin binds to the receptor which causes phosphorylation of the intracellular tyrosine residues
  • this allows association with JAK2 and JAK2 activation allows the subsequent signalling pathways downstream to be activated.
  • Activation of STAT signalling molecules allows for gene transcriptional changes to occur.
  • IRS proteins which are insulin receptor sub proteins then activate PI3- Kinase
  • this then causes changes in channel function and gene transcriptional changes as well.
  • There is also activation in the Ras/MAPK pathway.
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7
Q

where are leptin receptors expressed in the CNS?

A

specific hypothalamic nuclei (ARC, VMH, DMN)

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8
Q

High levels of Ob-Rb mRNA/protein are expressed where?

A

in the cerebellum, hippocampus, brain stem and amygdala

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9
Q

how does leptin get into the brain?

A
  • saturable transportation
  • CSF
  • released locally in CNS as mRNA peptide
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10
Q

how do you locate leptin receptors?

A

immunocytochemical approach

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11
Q

how does immunocytochemical approaches work? (4)

A

Using specific antibodies that are targeted against particular receptor sites.

  • Take hippocampal neurons and fix and permeabilise them.
  • The antibody can now gain access to the neuron.
  • You can then visualise where this is localised using a secondary antibody with a fluorescent tag.
  • Then use a confocal microscope to give indication of where the receptors are localised.
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12
Q

leptin receptors colocalised with what?

A

NMDA receptors

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13
Q

how would you isolate excitatory transmission?

A

to look at dual component EPSPs you would block GABA-ergic transmission by bath applying picrotoxin. You’d have caesium ions in the patch pipette which will dialyse into the neurons and block GABAbRs.

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14
Q

what does leptin do to hippocampal synaptic plasticity?

A

facilitates it

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15
Q

how does leptin facilitate hippocampal synaptic plasticity?

A

enhances NMDA-induced Ca2+ influx

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16
Q

how does leptin modulate NMDAR function and how was this shown?

A

Using blocking agents they have identified that both activation of MAPK and PI3-kinase signalling contribute to the facilitation of NMDA responses by leptin receptor activation

(blocking agents= LY294002 or wortmannin (PI3-K), PD98059 or U0126 (MAPK))

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17
Q

which NMDAR subunit dictates biophysics and pharmacology?

A

NR2

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18
Q

where are NR2a and NR2b receptors expressed?

A

NR2a- synaptically

NR2b- extrasynaptically

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19
Q

how does leptin enhance maximal currents to NMDA responses?

A

leptin has somehow changed the density of NMDARs expressed at the membrane. it suggests that leptin has the ability to upregulate or promote receptor trafficking to the membrane.

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20
Q

how would you check if any trafficking events have occurred in leptin signalling?

A

immunocytochemistry approach

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21
Q

what does leptin do to NMDAR surface expression?

A

increases it

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22
Q

what does leptin do in adult hippocampal tissue?

A

causes enhancement of synaptic transmission but doesn’t wash out. It causes a leptin induced novel form of LTP that is long lasting.

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23
Q

what regions of AMPARs determine the trafficking properties?

A

specific c-terminal regions

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24
Q

what does leptin do to GLuA1 surface expression?

A

increases it

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25
Q

What are the mechanisms underlying leptin-induced LTP?

A
  • GluA1 and 2 are predominant subunits in hippocampus.
  • GluA1 are calcium permeable and display inward rectification (polyamine block) whereas GluA2 are calcium impermeable and display linear IV relationship.
  • Leptin-induced LTP involves insertion of GluA2 lacking AMPARs into synapses and increases in GluA1 surface expression in adult hippocampal slices
26
Q

Leptin-induced increase in surface GluA1 is accompanied by what?

A

increase in PIP3

27
Q

what are the possible signalling mechanisms underlying the effects of leptin regarding PIP3?

A

Leptin increases PIP3 levels via;

  • increasing PI3-K activity (converts PIP2 to PIP3)
  • inhibiting PTEN (converts PIP3 to PIP2)
28
Q

what can mimic the effects of leptin?

A

inhibition of PTEN (using BpV)

29
Q

Leptin-insensitive rodents (db/db mice; fa/fa rats) display what?

A

impaired hippocampal LTP and LTD

30
Q

what deficits do Zucker fa/fa rats have?

A

spatial memory deficits

31
Q

what are the reasons for the leptin system to be considered as a potential therapeutic target in AD? (3)

A
  • Circulating leptin levels are lower in AD patients and in transgenic mice with mutations linked to familial AD.
  • Leptin decreases b-amyloid levels in transgenic mice with elevated b-amyloid levels.
  • Leptin improves memory in a mouse model of b-amyloid toxicity (SAMPB).
32
Q

leptin prevents the detrimental effects of what?

A

Ab on hippocampal LTP

33
Q

why is Ab harmful?

A

it promotes AMPAR internalisation

34
Q

what effects does leptin 116-130 have? (2)

A
  • Leptin (116-130), like leptin, displays cognitive enhancing properties.
  • Leptin (116-130) mirrors the neuroprotective actions of leptin in preventing aberrant effects of Ab
35
Q

how does insulin conserve fuel peripherally?

A

enhances uptake, utilisation and storage of glucose

36
Q

describe the insulin receptor

A
  • the insulin receptor is a large transmembrane glycoprotein complex that consists of two a and two b subunits linked by disulphide bridges. - A subunits are extracellular and have an insulin binding domain.
  • B subunits are transmembrane proteins with intrinsic tyrosine kinase activity.
37
Q

how do you detect insulin receptor expression in the CNS experimentally? (3)

A
  • Immunocytochemistry (antibodies against IR subunits) are used to determine cellular localisation of IR.
  • In situ hybridisation [35S]dATP labelled antisense oligonucleotide probes for IR subunits. This detects IR mRNA in specific brain regions (NB, mRNA expression does not indicate functional protein).
  • Western blots and RT-PCR is used to determine specific localisation of IR mRNA and protein in different brain regions.
38
Q

How does peripherally-derived insulin get into the brain?

A
  • Insulin uses active transport to get across the blood brain barrier.
  • A saturable insulin transporter exists.
  • The insulin transporter is a regulated system (i.e. shut off during hibernation and altered with fasting and diabetes).
  • Insulin may also be released locally in the CNS.
  • Insulin mRNA is expressed in neurons and insulin is also released from neurons by depolarisation.
39
Q

what is the role of insulin in the CNS?

A

mediates cerebral glucose uptake, but only in glial cells, not in neurons plus numerous other neuronal functions.

40
Q

long-term hyper-insulinemia is a risk factor for what?

A

dementia

41
Q

High insulin levels result in what?

A

resistance to insulin- leading to reduced levels of insulin reaching the brain

42
Q

where are IRs concentrated in the brain?

A

hippocampus and amygdala

43
Q

what does the injection of streptozotocin, a diabetic-inducing agent into the brain do?

A

induces significant memory impairment

44
Q

what does insulin do to NMDAR single channel currents and NMDAR-mediated synaptic transmission

A

enhances them

45
Q

which recombinant isoforms does insulin enhance?

A

NR1/NR2a and NR1/NR2b

46
Q

describe Insulin receptor signal transduction

A
  • Insulin binds to a subunit causing autophosphorylation of the tyrosine residues on the b subunits.
  • This then stimulates tyrosine kinase activity of IR.
  • Phosphorylated IR triggers activation of different signalling cascades including: IRS proteins and various Src homology domain proteins (e.g. PI3-Kinases) and Shc (adaptor protin): mediates association of IR with Grb-2-SOS complex (and activates RAS/MAPK cascade).
47
Q

how does insulin enhance NMDAR surface expression?

A

Insulin increases exocytosis and inhibits endocytosis.

48
Q

what experiment suggests insulin works via the SNAP-25 mechanism?

A

Injection of botox into oocytes- this reduces insulin enhancement of NMDA currents

49
Q

how does botox reduce insulin enhancement of NMDA currents?

A
  • Botox cleaves SNAP-25 and prevents SNAP-25 dependent exocytosis.
  • PKC can directly phosphorylate SNAP-25.
  • Insulin stimulation of atypical PKC downstream of PI3-kinase may underlie this effect.
50
Q

what happens if you block the atypical PKC downstream of insulin?

A

this blocks insertion of NMDAR in the membrane.

51
Q

how does insulin enhance NMDA responses?

A

via PI3-kinase and MAPK signalling

52
Q

what are the effects of insulin on excitatory transmission?

A
  • Insulin facilitates NMDAR-mediated synaptic transmission in hippocampus –> this is likely to promote induction of LTP.
  • Insulin depresses AMPAR-mediated EPSCs in hippocampal neurons (by reducing surface AMPAR expression) –> this may contribute to/ modulate LTD.
53
Q

what do high concentrations of insulin do to synaptic plasticity?

A

induces LTD

54
Q

what does insulin do to AMPA EPSCs and NMDA EPSCs?

A

depresses AMPA EPSCs but not NMDA EPSPs

55
Q

how does insulin internalise AMPARs?

A

insulin reduced GluA2 but not GluA1 surface expression.
Insulin accelerated endocytosis of GluA2 subunits.
Increased endocytosis resulted in LTD of excitatory synaptic transmission.

56
Q

what does insulin promote to internalise AMPARs?

A

clathrin-mediated endocytosis

57
Q

what does treatment with insulin on Ab-derived diffusible ligands do?

A

reduces ADDL-induced synaptic loss

58
Q

what does insulin do on Ab-induced impairment of LTP?

A

inhibits it

59
Q

insulin plays a role in learning and memory as; (3)

A
  1. insulin receptor expression is upregulated
  2. Grb accumulates in the synaptic fraction
  3. P-MAPK is increased
60
Q

boosting insulin in the CNS may have benefits in AD as; (3)

A
  1. insulin is a cognitive enhancer
  2. insulin prevents AD-linked synaptic loss
  3. insulin prevents amyloid block of LTP

BS42018- Mapping Memories in the Brain (4 decks)

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