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BMSc - Neuropharmacology and Behaviour > Hormonal Regulation of Synaptic Plasticity > Flashcards

Hormonal Regulation of Synaptic Plasticity Flashcards

1
Q

Can LTP be modulated?

A

Yes; the degree and duration can be influenced

Numerous neuromodulators and nT can affect; the threshold for LTP induction or the magnitude +/- magnitude and duration of LTP

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2
Q

What 2 endocrine hormones markedly influence hippocampal synaptic plasticity?

A

Leptin

Inslulin

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3
Q

What is Leptin?

A

“Fat controller”
16 kDa protein encoded by ob gene

Primarily made and secreted by white adipose tissue

Circulates in amounts proportional to body weight

Regulates energy homeostasis via its actions at the hypothalamus

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4
Q

Describe the leptin receptor

A 
Product of the diabetes (db) gene 
Member of class 1 cytokine superfamily

Multiple splice variants (LepRa - LpRf)
All transmembrane receptors except LepRe (carrier for leptin in plasma)
LepRb (contains tyrosine residues). Long C terminal domain which contains tyrosine residues enabling full complement of leptin receptor signalling

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5
Q

Describe the signalling pathway of leptin receptor signal transduction

A

Jak2 is phosphorylated
Ras/raf/MAPK kinase
PI-3 kinase
STAT3

Gene transcription and ion channel influence

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6
Q

Where are leptin receptors expressed within the brain?

A

Specific hypothalamis nuclei (ARC, VHM, DMN = energy balance)

mRNA/protein in cerebellum, hippocampus, brain stem and amygdala

Role of lepin receptors at these extra-hypothalamic areas is unclear

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7
Q

How does leptin enter the brain?

A

Main route: saturable transport system via triglycerides

Short LepR isoforms; expressed on brain microvessels, these isoforms bind and internalize leptin

Leptin also reaches the brain via CSF

Lepin can be made and released locally in the CNS; as lepin mRNA and protein are widely expressed within the brain

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8
Q

How can the detection of ltpin production be detected in hippocampal neurons?

A

Immunocytochemical methods

Fixed and permabalised

Exposed to primary Ab against leptin receptor

Secondary antibody with a fluorescent tag

Visualise with laser scanning confocal microscope to visualise the distribution of these rceptors

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9
Q

Describe the cellular distribution of leptin receptors on hippocampal neurons

A

Expressed at hippocampal synapses

Marker for synapsin 1 (marker for presynaptic synapse)

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10
Q

Is there an association with lepin receptors and NMDA?

A

Yes; they co-localise

Specifically NR2A

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11
Q

What responses are observed from the Ca1 region?

A

Dual component EPSC; fast AMPAR EPSC and a slower NMDAR EPSC

GABAergic transmission inhibited by picrotoxin and Cs+ in patch pipette

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12
Q

What is the impact of leptin on hippocampal synaptic plasticity?

A

Theta burst stimulation protocol

Normal EPSC = short term potentiation; peak then decay

Leptin; small depression in EPSC but then with a theta burst there is a sharp peak which is sustained (LTP like process)

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13
Q

Is there a role for leptin in NMDAR mediated synaptic transmission?

A

If NMDAR component is isolated via blockade of AMPARs

Gradual then sustained increase in NMDAR conduction

Leptin enhances NMDAR mediated LTP

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14
Q

What is fura 2am?

A

Race metric calcium dye; measures intracellular calcium levels

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15
Q

Does leptin influence calcium influx?

A

Yes; it enhances NMDA induced calcium influx
Monitored via fura-2am

Leptin facilitates this calcium rise via NMDAR activation

Shanley et al; 2001

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16
Q

What are the pathways that allow leptin to modulate NMDAR function?

A

JAK2
Ras/Raf

PI-3 kinase

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17
Q

What is the molecular composition of NMDARs?

A

At least one GluN1 with one or more GluN2
Can exist with or without a GluN3 subunit

GluN2 subunits determine the biophysics and pharmacology of NMDARS

In hippocampus; NR2A and NR2B

NR2A = synaptic

NR2B = extrasynaptic

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18
Q

Can leptin influence NMDAR evoked currents via NMDAR subunits?

A

2 electrode voltage clamp receptors in xenopus oocytes

Expression of NR1a and NR2A alone (no leptin receptors); leptin has no impact on NMDAR current

Expression of NR1a/NR2A + Ob-R; leptin can facilitate NMDAR mediated responses due to activation of these leptin receptors

Furthermore, leptin is able to facilitate a maximal NR1A/ NR2A mediated currents.

Leptin can influence expression of NMDARs at membrane of oocytes

Leptin increases NMDAR receptor surface expression (within 5 mins)

Harvey et al (2005)

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19
Q

Summarise the effect of leptin at NMDAR receptors?

A

Leptin enhances NMDAR function and facilitates synaptic plasticity (Shanley et al; 2001)

Leptin modulates NMDAR function which involves PI1 kinase and MAPK

Enhanced trafficking of NMDARs contributes to the effects of leptin (Harvey et al; 2005)

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20
Q

Is there a difference in leptin activity at excitatory synapses in younger or older mice?

A

Juvenile studies; leptin to hippocampal slices; depression in synaptic strength which resolves with washout

Adult mice; facilitates an increase in EPSC which is sustained with washout

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21
Q

Describe the molecular composition of AMPARs

A

Tetrameric complex of 4 subunits (GluA1-4)

Cytoplasmic C-terminal tails are key for regulation of AMPAR function

GluA1 +4 = long tails
GluA2 +3 = short tails

Specific C-terminal regions determine the trafficking properties of AMPAR complexes

GluA1: calcium permeable, displays inward rectification due to polyamine block

GluA2; calcium impermeable, linear current-voltage relationship

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22
Q

Does leptin have an influence on GluA1 expression?

A

Yes; leptin increases GluA1 surface expression

Moult et al 2010

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23
Q

What are the mechanisms that underlie leptin induced LTP

A

Insertion of GluA2-lacking AMPARs into synapse

Moult et al (2010)

You can determine this via recording of the rectification index

Increase in GluA1 surface expression in adult hippocampal slices

Leptin promoters GluA1 trafficking to the synapses (immunocytochemistry)

Leptin induced increase in surface GluA1 is accompanied by an increase in PIP3

Inhibition of PTEN mimics the effects of leptin

Leptin occludes the effects of BpV on synaptic strength (selectively inhibits PTEN)

Inhibition of PETN mimics and occludes the effects of leptin

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24
Q

Describe the role of PI 3K?

A

Involved with trafficking of AMPARs to synapse

PIP3- signalling molecule to activate downstream signalling molecules and kinases

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25
Q

How does leptin increase PIP3 levels?

A

Leptin increases PIP3 levels via increased PI3-kinase activity

Leptin increases PIP3 levels via inhibition of PTEN

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26
Q

Summarise the effects of leptin on AMPARs

A

Increasing excitatory synaptic strength via increasing GluA1 surface expression

Increase in surface GluA1 is assoc with an increase in PIP3 levels

Inhibition of PTEN mimics and occludes the effects of leptin

Leptin regulation of surface GluA1 involves PTEN inhibition

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27
Q

Overall, summarise the effects of leptin at the synaptic level

A

Facilitates hippocampal LTP via enhancement of NMDAR function

Leptin driven changes in dendritic morphology may contribute to increases in synaptic strength

Trafficking of GluA1 subunits is likely to underlie leptin facilitation of synaptic strength

Leptin inhibition of PTEN underlies trafficking of GluA1 to CA1 synapses

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28
Q

Is there a role for leptin in hippocampal dependent learning and memory?

A

Leptin insensitive rodents (db/db mice; fa/fa rats) display impaired hippocampal LTP and LTD

Direct administration of leptin into the hippocampus improves memory processing (wayer et al; 2004)

Diabetics often display cognitive impairments (increased risk of AD); obesity (leptin resistance) is a common risk factor for T2DM (gispen et al 2000)

29
Q

What can be seen in leptin insensitive rodents hippocampal LTP?

A 
Zucker lean (normal leptin function): HFS, induced robust LTP 
Zucker fa/fa (leptin insensitivity); HFS, marked reduction in hippocampal LTP
30
Q

Are there behavioral impact associated with this reduction in hippocampal LTP within zucker fa/fa animals?

A

Yes; spatial memory deficits

Longer swimming distance in fa/fa animals in MWM

Fewer crossings of original platform locations in fa/fa rats than controls

No difference in swimming speed between fa/fa rats and cntl rats

31
Q

Is there a therapeutic potential of leptin?

A

Leptin modulates plasticity of hippocampal excitatory circuits and is a potential cognitive enhancer

AD?

  • Circulant levels of leptin are lower in AD patients and tg mice with fAD
  • Leptin decrease beta amyloid levels in tg mice with elevated b-amyloid load
  • Leptin improves memory in a mouse model of b-amyloid toxicity
32
Q

Can leptin influence LTP in AD/ amyloid beta slices?

A

Doherty et al (2013); leptin can prevent the detrimental effects of AB on hippocampal LTP

33
Q

Can amyloid interfere with AMPAR trafficking?

A

Yes; AB promotes AMPAR internalization (hu et al; 2009)

Leptin can prevent this AB induced internalization (Doherty et al; 2013)

34
Q

Conclude the ability of leptin as a therapeutic

A

Reduced detrimental effects of Ab on synaptic plasticity
Leptin prevents AB induced internalisation of AMPARs
Leptin system is a potential novel target for AD

Specific fragments of leptin peptide mimic the anti-obesity actions of leptin

Small-leptin fragments that mimic the cognitive enhancing and neuroprotective actions of leptin may have therapeutic effects in AD

35
Q

Can leptin fragments mimic leptin action?

A

Yes; Malekizadeh et al (2017)
Amino acids 22-56 and 116-130

116-130 is involved with assay of increasing surface expression of GluA1

Leptin (116-130); protects against the aberrant effects of AB

36
Q

Conclude the evidence for leptin fragments and their therapeutic benefits

A

Leptin (116-130) displays cognitive enhancing properties

Leptin (116-130) mirrors the neuroprotective effect of leptin against AB

Establishes further the role of the leptin system as a therapeutic target for AD

Leptin (116-130) is a possible template for small molecules that mimic leptin action

37
Q

What are the peripheral actions of insulin?

A

Main hormone that controls intermediate metabolism having actions in liver, muscle and fat

Conserves fuel by enhancing uptake, utilisation and storage of glucose

Growing evidence that insulin has widespread actions in the CNS

38
Q

Describe the insulin receptor

A

Large transmembrane glycoprotein complex
Consists of two alpha and two beta subunits linked by a disulphide bride

Alpha subunit: extracellular and have an insulin binding domain

Beta subunit; transmembrane protein with intrinsic tyrosine kinase activity

39
Q

How can the insulin receptor expression be investigated within the CNS?

A

Immunocytochemistry; antibodies against IR subunits to determine cellular localisation of IR

In situ hybridisation: [S]dATP labelled antisense oligonucleotide probes for IR subunit. This detects IR mRNA in specific brain regions (NB. mRNA expression does not indicate functional protein)

Western blots and PT-PCR; used to determine specific localisation of IR mRNA and protein within different brain regions

40
Q

Are insulin receptors present within the hippocampus?

A

Schwartz et al; 1992: Insulin receptor immunolabelling and mRNA expressed in the hippocampus

Havrankova et al; 1978: expression of insulin mRNA in the hippocampal neurons

Folli and Baskin; 1994: key components of the insulin receptor driven signalling pathways (IRS protein and PI 3-kinase) have been found in the hippocampus

41
Q

Describe the work of Zhao et al (1999) who used in situ hybridization to localise IR mRNA

A

IR mRNA present in the hippocampal CA1 cells

42
Q

What is MAP-2?

A

Somatodendritic marker

43
Q

Where on the neuron does the IR localie?

A

Good expression on neurons

Synapsin 1 and IR co-localise, and therefore they localise at the synapse

44
Q

How does the peripherally driven insulin enter the brain?

A

Active transport across the BBB

Saturable insulin transporter exists

Insulin transporter is a regulated system i.e. shut off during hibernation and alerted with fasting and diabetes

Insulin can also be released locally within the CNS:

Insulin mRNA expressed in neurons

Insulin released from neurons by depolarisation

45
Q

What is the functional role of insulin within the CNS?

A

In periphery: regulated glucose metabolism

CNS: insulin mediates cerebral glucose uptake but only in glial cells, not neurons

Insulin has effects on hippocampal synaptic function

46
Q

Is there a role for insulin in learning and memory?

A

Epidemiology studies indicate that long term hyper-insulinemia is a risk factor for dementia

High insulin levels results in a resistance to insulin - and therefore a reduced level of insulin to the brain

Craft et al; 1999: insulin administration to healthy individuals (glucose levels kept constant) improves memory formation

47
Q

How does insulin influence learning and memory?

A

IRs are concentrated in brain regions involved in learning and memory (hippocampus and amygdala)

Man et al; 2000: insulin induces changes in excitatory synaptic strength

Injection of streptozotocin, a diabetic inducing agent into the brain results in significant memory impairment

Defective insulin action has been reported in AD (metabolic imbalance in AD)

T2DM; impairment of cognitive function is well documented

48
Q

Does insulin modulate NMDAR function?

A

Yes;
Facilitates native NMDAR responses (hippocampal)
Recombinant NMDAR mediated currents

Insulin enhances:

  • NMDAR single channel currents
  • NMDAR mediated synaptic transmission

Insulin selectively enhances NR1/NR2A and NR1/NR2B recombinant NMDAR isoforms (Lui et al; 1995)

49
Q

Does insulin potentiate NMDAR currents?

A

Skeberdis et al; 20001:
Xenopus oocytes expressing NR1-4a/ NR2A subunits, under -60mV voltage clamp

  • Insulin enhances the inward currents evoked by NMDAR
  • The general tyrosine kinase inhibitor, genistein did not prevent insulin action
  • Tyrphostin A47, a selective inhibitory or IR tyrosine kinase blocked insulin action
50
Q

Describe IR signal transduction

A

Insulin binds to alpha subunit causing autophosphorylation of tyrosine residues on beta subunits

This stimulates intrinsic tyrosine kinase activity of IR

Phosphorylated IR triggers activation of different signalling cascades including: IRS proteins and various Src homology domain proteins (PI3-kinase)

Shc (adaptor protein); mediates association of IR with Grb-2SOS complex (activates Ras-Raf-MAPK cascade)

51
Q

Do the signalling pathways that mediate insulin facilitate NMADR responses?

A

Skeberdis et al 2001: tyrphostin blocks NMDAR responses

Liao et al; 1999; PKC inhibitors block insulin action at NMDARs

Liao and Leonard; 1999: Src TK inhibitors block insulin action at NMDARs

Christie et al 1999: insulin causes tyrosine phosphorylation of NR2A/ NR2B subunits

52
Q

Does insulin enhance the surface expression of NMDARS?

A

Skeberdis et al; 2001:

Recordings from oocytes expressing NR1-4a/ NR2A. Insulin increases maximal NMDAR currents

Insulin increased number of functional channels/ cells. Currents recorded in MK-801 (use dependent NMDAR antagonist). NMDAR currents peaked and they decayed as the channels opened and were blocked by MK-801. Cumulative charge transfer, Q (area under curve) is larger after insulin indicating an increase in no. of NMDAR channels

Normalised currents to analyse decay time constants. Insulin did not change decay time i.e. no change in NMDAR channel kinetics

53
Q

How does insulin act to increased NMDAR surface expression?

A

Skeberdis et al; 2001

Increases exocytosis of NMDARs:

  • Injection of botox into oocytes reduced insulin enhancement of NMSAR currents
  • Botox cleaves SNAP-25 and prevents SNAP-25 dependent exocytosis
  • PKC can directly phosphorylate SNAP-25. Insulin simulation of atypical PKC downstream of PI 3-kinase may underlie this effect
54
Q

Using calcium imaging studies, can insulin modulate Ca2+ influx via NMDAR channels?

A

Neurons loaded with Ca2+ sensitive dye, Fura 2-AM

CCD-based imaging system used to measure changes in Ca2+

55
Q

What signalling pathways are involved with the insulin induced NMDAR responses?

A

PI 3-kinase

MAPK

56
Q

Summarise the effects of insulin potentiation of NMDARs

A

Insulin does not affect basal Ca2+ levels

Insulin potentiates NMDAR induced Ca2+ influx in a reproducible and reversible manner

Inhibitors of PI 3-kinase and MAPK (ERK) attenuate this action

Increased NMDAR exocytosis and trafficking to cell membrane

57
Q

Describe the impact of insulin on excitatory synaptic transmission

A

Insulin facilitates NMDAR mediated synaptic transmission = promotion of LTP induction

Man et al; 2000
- Insulin depresses AMPAR mediated EPSCs in the hippocampal neurons (reducing surface AMPAR expression) = modulates LTD

58
Q

Does insulin induce LTD?

A

Huang et al 2004:

Insulin can induce a novel form of hippocampal LTD

Concentration dependent effects of insulin on synaptic efficacy

Low conc of insulin = transient synaptic depression

High concentrations = LTD

59
Q

What receptor does insulin LTD involve?

A

Huang et al; 2004

IR; not IGF-1R

Insulin induced LTD is unaffected by anti-IGF1 Ab

IGF-1 induced LTD is blocked by anti-IGF1 antibody

60
Q

Where is this form of insulin induced LTD expressed?

A

Post-synaptic locus of expression

Depresses AMPAR EPSCs but not NMDAR EPSCs

61
Q

Describe the role for AMPAR internalization in insulin induced LTD

A

Man et al (2000); insulin reduced GluA2 but not GluA1 surface expression

Insulin accelerates endocytosis of GluA2 subunits

Increased endocytosis results in LTD of excitatory synaptic transmission

Surface Rs labeled with Ab in non-permanent conditions (green). Total Rs were probed under permeant conditions

Insulin has no effect on GluA1 but results in a reduction of GluA2 surface expression

Insulin promotes clathrin mediated endocytosis of AMPARs;
Surface AMPARs are pre-labelled with a time dependent reduction in surface AMPARs
Insulin accelerates the loss of AMPARs compared to control

Hypertonic sucrose blocked insulin induced loss of surface AMPARs

62
Q

How does AMPAR internalization occur?

A

Involves a series of events;
Formation of clathrin coated vehicles and an intracellular pool of receptors

Hypertonic sucrose can block this

63
Q

Summarise the role of insulin on AMPARs

A

Man et al; 2000:

Insulin inhibits AMPARs but not NMDAR EPSCs

IV curves show that insulin reduces EPSC currents

Insulin induced LTD is dependent on post-synaptic activation of IR

Insulin induced LTD can be blocked by postsynaptic dialysis with IR neutralising Ab (anti-IR)

64
Q

Summarise the role of insulin on LTD

A

Induces a novel form of hippocampal LTD which is expressed post-synaptically

This process involved PTK, PI 3-kinase and PCK

Involves internalization of Glu-A2 containing AMPARs

65
Q

Is there a role for insulin during learning and memory in rodents?

A

Zhao et al (1999): examined changes in IR expression, tyrosine phosphorylation and IR signalling molecules after training in MWM

Training upregulated IR mRNA and protein levels with CA1 and dentate gyrus

An increased in IR immunostaining

After training, staining was clustered within specific intracellular compartments, compared with an even distribution in control animals

66
Q

Describe the biochemical changes that occur following MWM training (insulin)

A

Zhao et al (1999):
- 2 proteins (52 and 66 KDa) showed an increase in tyrosine phosphorylation after training

One protein: Shc-66 co-precipitated with IR suggesting these 2 proteins associate in vivo after training

Significant accumulation of Grb (52 KDa) in hippocampal synaptic membrane function

Increase in active form of MAPK were also detected

Spatial training induces a number of changed within the insulin system

67
Q

Is there a link between insulin and neurodegenerative disorders?

A

Insulin has cognitive enhancing properties

T2DM; cognitive impairment and AD like phenotype

De Felice et al 2009; bolstering of brain insulin signalling could have significant potential to slow or deter AD

68
Q

Describe the link between insulin and ADDL

A

De Felice et al; 2009:

AB derived diffusible ligands (ADDLS) induce hippocampal synaptic loss

Treatment with insulin prevents this loss

Lee et al 2009:
- HPS induced LTP in control slices, but failed to induce LTD in AB-1-42

Co-incubation of slices with insulin prevents this AB1-42 induced block of LTP

Incubation of insulin alone had no significant effect on the LTP induction

69
Q

Summarise the role of insulin in AD

A

Cognitive enhancing properties

Insulin markedly influences hippocampal synaptic plasticity and glutamate receptor trafficking

Insulin (like leptin) reduced detrimental effects of AB on synaptic plasticity (LTP and LTD)

Insulin prevents AB induced hippocampal synapse loss

Insulin system is a potential novel therapeutic target for AD

BMSc - Neuropharmacology and Behaviour (27 decks)

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