Hormonal Regulation of Synaptic Plasticity Flashcards

Question

How does leptin increase PIP3 levels?

Answer 1

Leptin increases PIP3 levels via increased PI3-kinase activity Leptin increases PIP3 levels via inhibition of PTEN

Answer 2

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

Answer 3

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

Answer 4

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)

Answer 5

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

Answer 6

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

Answer 7

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

Answer 8

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

Answer 9

Yes; AB promotes AMPAR internalization (hu et al; 2009) Leptin can prevent this AB induced internalization (Doherty et al; 2013)

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

IR mRNA present in the hippocampal CA1 cells

Answer 18

Somatodendritic marker

Answer 19

Good expression on neurons Synapsin 1 and IR co-localise, and therefore they localise at the synapse

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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)

Answer 25

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

Answer 26

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)

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

Neurons loaded with Ca2+ sensitive dye, Fura 2-AM CCD-based imaging system used to measure changes in Ca2+

Answer 31

PI 3-kinase | MAPK

Answer 32

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

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

Post-synaptic locus of expression Depresses AMPAR EPSCs but not NMDAR EPSCs

Answer 37

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

Answer 38

Involves a series of events; Formation of clathrin coated vehicles and an intracellular pool of receptors Hypertonic sucrose can block this

Answer 39

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)

Answer 40

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

Answer 41

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

Answer 42

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

Answer 43

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

Answer 44

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

Answer 45

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