Molecular Mechanisms for LTP Flashcards
What is happening at the molecular level which explains the rapid change of the neuron?
Critical thing is the difference glutamate has at normal neuronal transmission and when the membrane is in an excited state - it all happens when NMDA receptors are activated
What is the main difference when NMDA is activated?
Calcium enters the cell through NMDA channel, which triggers a pathway of events - changes the properties of the post-synaptic cell, so the next time it is activated, it has a different response
What does calcium do?
Activates an enzyme which is in the post-synaptic terminal - Calcium calmodulin-dependent protein kinase 11 (CaMK11)
What does CaMK11 do?
Phosphorylates existing AMPA receptors
Stimulates the insertion of new AMPA receptors into the membrane
What does phosphorylatating existing AMPA receptors mean?
Makes a chemical change to other proteins in the area - it makes the AMPA receptors more efficient, so that there is an immediate response of the AMPA receptors to glutamate
when glutamate binds, AMPA channel opens more efficiently and opens for longer, so there is more sodium influx, leading to greater EPSP
What does stimulation of insertion of new AMPA receptors mean?
It activates an intracellular pathway, within the post synaptic cell, there will be internal pools of receptors ready to be inserted into the membrane, it causes the insertion of more AMPA receptors, which means more will become phosphorylated
What happens just from calcium entering the post synaptic neuron?
Activate the protein CaMK11
There are immediately more AMPA receptors, which are more efficient. Increases the size of EPSPs
What is the change called which is occurring at the synapse?
Long term potentiation - modifying how AMPA responds
What is the difference in AMPA receptors before and after LTP?
Before - few AMPA, small EPSP’s
After - more AMPA receptors, more effective, larger EPSP’s, LTP
How does CaMK11 do this?
It has a molecular switch, which is sustained after depolarisation
What does it mean that CaMK11 has a molecular switch?
Once it is activated my calcium, it has autocatalytic activity - means it phosphorylates itself. When phosphorylated is active, it no longer requires calcium. This maintains phosphorylation, insertion of AMPA receptors, after the depolarising stimulus has gone back to normal
What is the role of the molecular switch?
To maintain the increased excitability of the neuron for minutes to hours
How does LTP occur in the pre synaptic neuron?
The post synaptic neuron can feed back to presynaptic neuron by retrograde neurotransmitter - Nitric oxide
Steps which happen in pre synaptic cell
Calcium enters through NMDA and activates Nitric oxide synthase (makes this game)
NO diffuses from the site of production into the presynaptic cell, activating guanylyl cyclase in the presynaptic terminal
Guanylyl cyclase produces the second messenger cGMP
This pathway leads to a signal transduction cascade, so there is increased glutamate release from the synaptic bouton
What happens to the pre synaptic neuron and the post synaptic neuron?
The pre synaptic neuron releases more glutamate, and the post synaptic neuron has a greater response
How does late phase LTP work?
Requires protein synthesis to occur, new proteins are made which changes the protein
How can you get long-lasting LTP?
Through protein synthesis
What are the stages of memory formation?
Acquisition
Consolidation
Recall
How do we know protein synthesis is important?
Protein synthesis inhibitors prevent the consolidation of longterm memories and LTP - EPSP goes down, they won’t remember anything
When recalling information, protein synthesis inhibitor injected post-acquisition (training) inhibits recall - shows it is necessary for consolidation
How does protein synthesis aid consolidation?
Through CREB (a transcription factor) which is activated by phosphorlyation and is phospholyated by kinases (PKA, CaMK11 etc)
What does CREB do?
Once it is phospholated, it allows other genes to be activated, which are specifically only activated in a situation where CREB is activated - so when LTP occurs, there are lots of new proteins being made
Difference between early phase LTP and late phase LTP?
Early phase - lasts a minute to an hour, explained by the actions of Ca2+ through NMDA receptor and enhancement of AMPA, presynaptic events etc
Late phase - lasts hours, days or months, requires new protein synthesis and can involve changes and new synpases - increase connections
How are new synapses recruited?
Before LTP, have some silent synpases
After LTP - the build up of EPSP’s in the synapse would spread to neighbouring synapses, repeatition will lead to depolarising other neurons. Unused AMPA receptors ae recruited. Then the synapses start responding to glutamate. After, there are 3 synapses with AMPA receptors in, the response has been tripped under normal conditions
What is a silent synapse?
Synpases which only have NMDA receptors, because after glutamate release, can’t fire an EPSP
How does LTP cause neighbouring synapses to be strengthened?
Before LTP - silent synpases
After LTP - EPSPs spread to neighbours, recruiting their AMPA receptors - new connections
Evidence of new synaptic connections following titanic stimulation
Before - no dendritic spines
After - formation of new dendritic spines, after 2 hours
What is the opposite to LTP?
Long term depression
Why is there an opposite?
Need a balance, homeostasis, need to be able to forget somethings and remember more important things
What does low frequency stimulation cause?
Decrease in EPSP amplitude when there is further stimulation
What is involved in LTD?
NMDA dependent
AMPA receptors are dephosphorlyated and removed
Due to low levels of calcium, activating phosphatase not kinase
