Synaptic Plasticity Flashcards
Evidence of depression following enhancement
PSP generation at high, medium and low calcium concentrations
Where are Munc13 and synaptotagmin involved
Synaptotagmin: prepares vesicular release- involved in Facilitation
Munc13-1: depression
Munc13-2: augmentation/potentiation
Munc13-1 role evidence
Munc13-1 KO evidence
Reduced depression after EPSCs/ IPSCs generated
Knock in of Calmodulin-insensitive Munc13-1 in mice
Reduced vesicle recovery time (presynaptic membrane capacitance and AMPAr mediated EPSCs)
Slower recovery from depression
Is a similar response to CaM inhibition in KOs
Munc13-2 role evidence
Munc13-2 KO
Reduced ability to induce augmentation
Rescue restored some augmentation
Mutant CaM insensitive 13-2 (W387R)
-Showed no augmentation
Calcium-sensitive domains of P/Q channels: role
IM Domain: facilitation and potentiation
CBD Domain: Depression
IM domain role evidence
Mutated IM domain shows reduced induction of facilitation and potentiation
-At low calcium levels, Ca2+ interacts with IM to induce P/Q channel activity
CBD domain role evidence
Mutated CBD domain shows no induction of depression
- At high calcium levels, Ca2+ interacts with CBD to reduce P/Q channel activity
- Not limited by vesicle release upon HFS
Theory of multiple mechanisms of Short term plasticity (Cheng 2008)
Deletion of both Calcium sensitive domains still leaves some enhancement and depression
There may be other factors which contribute to control
Hippocampal model of plasticity
Prolonged stimulation of perforant path
- Elevated EPSP production in CA1 maintained for 3 hours
- NMDA antagonist APV blocked
NMDA independent LTP in Hippocampal mossy fibres
Mossy fibres (Dentate gyrus granule cells project to CA3 pyramidal cells) Lack NMDA receptors, glutamate acts upon mGluRs and Kainate receptors Presynaptic calcium entry directly increases cAMP R type channels may mediate this effect (blocking P/Q does nothing)
Synaptic enlargement over time
Spines increase in size, produce increased EPSPs
Changes in AMPA subunit expression
Induction: mGluR1 homomers
- Greater inward current- naturally blocked by polyamine
Over time: replaced by mGluR1/mGluR2 heteromers
- Greater outward current (mGluR2 prevents influx)
LTP in inhibitory synapses
HFS IPSPs generated
Calcium and NMDA dependent
Not GABA dependent
Nitric oxide as a second messenger and opioids
Inhibition of synthesis (L-NAME)
Stimulation of synthesis (SNAP)
Opioids prevent IPSC administration
Upstream of cGMP production (administration reduces this effect)
Nitric oxide in alzheimers disease
Early AD
Increased vesicle release (EPSPSs)
L-NAME abolishes late LTP and reduces pre-pulse facilitation
Late AD
NO forms reactive oxygen species which are implicated in AD, depleting vesicular pools/reserves and accelerating disease progression
mGluR dependent LTD
Presynaptic- mGluR2
Decreases cAMP, common in mossy fibres/cerebellum
Post-synaptic- mGluR2
Endocannabinoid and downstream effects
Agonism (WIN) and Antagonism (AM251) of CB1 receptors
CB1: induces LTD by activating PKA/cAMP
Reduced mIPSCs when PKA antagonised
Targets RIM-alpha (synaptic release machinery)
RIM-A KO reduces inhibitory LTD production
TRPV1 mediated LTD
Capsacin
Antagonism/ KOs reduced effect
Calcineurin dependent
-Blocked by Cyclosporin A
12-S-HPETE role
Potential natural agonist of TRPV1
-KO/Antagonism
Optogenetic fear pairing and memory
Shock paired with sound, also with optogenetic stimulation
Training reduces lever presses
Optogenetic LTD- increased lever presses (mice forget)
Optogenetic LTP- reduced lever presses (mice remember again)
Anisomycin and Actinomycin
Asinomycin (protein synthesis inhibitor)
Prevents initial EPSP spike but is maintained
Actinomycin (mRNA synthesis inhibitor)
EPSP spike but not maintained
Initiation factors role
Phosphorylation of eif21s1 by DHPG induces LTD
Mutation of phosphorylation site Ser-Ala prevents this
Synaptic tagging theory
Staufen staining- colocalises mRNA with actin
CREB action
Forskolin (cAMP agonist)
Western blot increased pCREB with KCl
Fear shock conditioning LaCZ (B-galactoside reporter)
Morris Water Maze KOs reduced performance
BDNF and CREB
BDNF- growth of inhibitory synapses
Mutation of CREB binding site
- reduced CREB/RNA Pol II binding
- reduced mRNA and glut
- less staining of GABAergic synapses/ colocalisation of markers (GAD65, VGAT)
NFAT role
CaN activated
Dopamine agonist increases NFAT activity (Luciferase)
Nifedipine decreases NFAT activity (Luciferase)
Enhances GluR2 expression
- Increased luciferase activity in constitutively active mutant
- Increased AMPA current
- mutant glur2 reduced activity
Cocaine and NFAT
Other cocaine effects
Increased NFATc4 translocation in cocaine use (western blot)
Due to increased dopaminergic activation in striatum
Increases H3K9 methyltransferase expression- increased gene expression
DNA methylation evidence
DNMT inhibitor (Zebularine)- reduced LTP
Fear conditioning- reduces PPI methylation Inhibiting methylation (Zebularine) reduces fear conditioning response
Reelin methylation reduced in response to fear conditioning
Methylation in hippocampus reverts to baseline after 24h
Histone acetylation evidence
Fear conditioned mice- increased acetylation (Western blot)
HDAC2 O/E Morris Watermaze test performance reduced, less LTP
HDAC2KO/ Inhibition (Trichostatin A)
HDAC and alzheimers
APP overexpression model increased HDAC2
Sodium butyrate (inhibitor) restores function
Improved memory in WTs
P25 OE: HDAC2 KOs similar to WTs in Morris water maze/fear conditioning
HDAC4
Class 2a HDAC
Represses genes (neurotransmission, AMPA receptor trafficking) involved in synaptic transmission
Mutation assc. with Bradydactyly Mental retardation; cerebellar and visual neurodegeneration
Histone H2A.Z subunit exchange
Presence of H2A.Z subunit appears to negatively affect plasticity
- Fear conditioning: reduced h2afz gene expression
- Depletion of H2A.Z in rats using AAV improved fear conditioning
- Restrictive effect on memory creation
Histone methylation
H3K4 increases expression
H3K9 decreases expression
fear conditioning performance
