Lecture 22- Post Synaptic Mechanism/ modulation Flashcards
Is long term potention are pre-synaptic or post-synaptic mechanism?
Post-synaptic
What opposes LTP?
-LTD (Synaptic transmission weakening)
How does LTD occur?
- Repetitive low frequency stimulation results in a low level Ca2+influx through NMDARs
- Low levels of Ca2+ activate protein phosphatases
- Remove phosphates from AMPA receptor and other targets
- Removes AMPA receptors from membrane
- Also, long term changes to gene expression
What exists to balance the processes of LTP and LTD?
Modulation: Preserves a relative enhancement of synaptic transmission
What is the debate regarding the Mechanisms underpinning long-lasting synaptic change?
-Whether it occurs presynaptically (Neurotransmitter release)
-or postsynaptically (Receptor trafficking, local protein synthesis, gene expression, receptors)
For the AMPA-subtype of glutamate receptors what are AMPAR subunits? How do they assemble?
- GluA1–GluA4
- Assemble as dimers-of-dimers to form
- hetero-tetrameric receptors
or - homomeric receptors (GluA1)
What is the effect of glutamate binding to AMPA- receptors?
Glutamate binding opens the channel
- Influx of Na+ ions
- Efflux of K+
- Depolarization
How are the AMPA-subtype of glutamate receptors regulated?
GluA2 subunits undergo RNA editing
* Glutamine - arginine (Q/R editing)
* Prevents Ca2+-influx
GluA2-containing AMPARs are largely Ca2+- impermeable
* GluA2-lacking AMPARs are Ca2+ permeable
Phosphorylation of GluA1 by CaMKII
* Serine831 enhances single channel conductance
Phosphorylation GluA1 by PKA
* Serine845 enhances open probability and important for
retention at the plasma membrane
What is the lasting effect of strong NMDAR activation?
An increase in number of AMPARs at activated synapses
What is meant by the phrase that AMPARs are highly dynamic? What does this mean?
AMPARs shuttle into (or out of) synapses
* Results in long-lasting changes in synaptic strength
Lateral mobility
*Along the cell surface
* Between synaptic and extra-synaptic regions
Means=
* Increased trafficking to the PSD
* Increased retention in the PSD
What are AMPARs a part of?
-Complex protein networks
-So have increased
association with regulatory
molecules when modulated by LTP
How are AMPARs synthesized?
Local protein synthesis:
* Polyribosomes are found in spines
* Polyribosomes translocate from dendritic
shafts to spines in response to activity
* mRNA is found in dendrites
* mRNA is translated in response to activity
Glutamate receptors are synthesised locally
from pre-existing mRNA
What is CREB and what is it’s function?
cAMP response element binding protein
- initiates new gene expression
What are intermediate early genes? What do they do?
-Transcription factors: Egr1, AP1(fos/jun)
-Amplification of gene expression
What are Secondary response genes? What do they do?
Receptors and many others
-New synapses
-Larger synapses
-Re-structured synapses?
What do lasting memories require?
-New gene expression
What changes occur immediately and then after time in terms of memories?
-Within hours-days= plasticity transcriptome i.e. synaptic restructuring, and an epigenetic blockage
-Within days- weeks= maintenance transcriptome
How does Alzheimer’s begin?
Begins with synaptic dysfunction
What is the amyloid Cascade Hypothesis for alzheimer’s?
-Amyloid-ß aggregation and plaque formation is the central event
-Leads to neuronal degeneration and
clinical symptoms
What ways does receptor dysfunction effect Alzheimer’s disease?
- Aβ causes an initial hyperexcitability of
neurons - due to spillover and excessive levels of glutamate in
the extrasynaptic space, leading to overstimulation
of NMDA receptors and subsequently synaptic loss
and cell death. - Aβ-induced endocytosis of the AMPA-type
glutamate receptors - leads to long-term depression
- Aβ disrupts actin dynamics
- leading to impairments in the trafficking of AMPA,
NMDA - Aβ interacts with adhesion molecules
- affects their expression and synaptic localization,
- impaired integrity of synapses
- leading to the disruption of neuronal networks in AD
What ways does receptor dysfunction effect Alzheimer’s disease?
- Aβ causes an initial hyperexcitability of
neurons - due to spillover and excessive levels of glutamate in
the extrasynaptic space, leading to overstimulation
of NMDA receptors and subsequently synaptic loss
and cell death. - Aβ-induced endocytosis of the AMPA-type
glutamate receptors - leads to long-term depression
- Aβ disrupts actin dynamics
- leading to impairments in the trafficking of AMPA,
NMDA - Aβ interacts with adhesion molecules
- affects their expression and synaptic localization,
- impaired integrity of synapses
- leading to the disruption of neuronal networks in AD
How might glutamate receptors be therapeutic targets for Alzheimer’s disease?
Memantine: antagonist of the NMDA receptor subtype of glutamate receptor. It is used to slow neurotoxicity.
- Researchers at Genentech recently developed a small molecule (GNE-0723) that selectively enhances GluN2A function, thus
boosting synaptic NMDAR signalling. - The researchers tested this in mouse models of Alzheimer’s
and epilepsy. - In both conditions, inhibitory interneurons flounder, leading to
too much synchronized neuronal activity. - Treatment reduced abnormal low-frequency oscillations and
epileptiform bursts - Improved Morris water maze performance
What does sAPPa do?
-enhances plasticity
-enhances protein synthesis
-enhances GluA1 synthesis
What is FUNCAT-PLA?
Fluorescence non-canonical amino acid tagging- proximity ligation assay:
-non-canonical amino acid taken up into cells and are labelled with proteins (only newly made ones are labelled).
-The proteins used are a nuclei acids. Have two so can hybridize creating a platform for fluorescent tag
-They are then localised using “click chemistry” & the
proximity ligation assay
