Lecture 34- Neuronal plasticity II Flashcards
What is the Hebbian hypothesis?
• Learning occurs when two connected neurons are active simultaneously in a way that strengthens the synaptic connection
-ie the strength between cell A and B gets stronger
• OR • “Cells that fire together, wire together”
-when A signals just before B
What does this prove?
- the importance of the hippocampus in memory
- right hippocampus activated when the cabbie is learning the route, and also when asked to tell how to get somewhere
- it is the site of memory consolidation
How does NMDA work?
- most of the synapses have all three types of glutamergic receptors, metabotropic, NMDA, AMPA (Kainate)
- NMDA opens only when two conditions are met, need glutamate binding and the removal of the Mg ion to be removed which happens via depolarisation of the membrane, the
- 70mV pulls the Mg+ into the receptor and when depolarised then freed -NMDA is 10 more leaky to calcium then AMPA, lets lot of it in
- There are similarities between conditions required for associative LTP and conditions required for NMDA receptor activation. Both require glutamate to be released at an already depolarised dendrite.
- Further, LTP requires calcium, and NMDA receptors provide a source of intracellular calcium. The Mg2+ “plug” is held in place by the strongly negative (-70 mV) membrane potential. When the membrane is depolarized near threshold (circa -50 mV), th electrostatic group is weakened, such that the Mg ion diffuses out of the pore
- . If glutamate binds at such a time, there will be inflow of cations, especially calcium (gCa ≈ 10X gNa)
What happens when glutamate is released onto the postsynaptic density?
- Note the presence of 3 types of glutamate receptors at excitatory junctions, When a glutamate vesicle is released, 5000 glutamate molecules are released and bind to all 3 types of glutamate receptor
1. AMPA receptors cause Na+ entry and depolarisation
2. NMDA receptors: nothing happens unless Mg is expelled, in which case Ca enters
3. mGluR receptors activate PLC via G-proteins Do you remember what PLC does?
What does PLC do?
- PLC targets PIP2 (2 fatty chains and soluble group in the cytoplasmic space= inositol bisphosphate)
- when activated PLC, create diglycerol and IP3
- IP3 makes calcium stores release from the intracellular stores
- another source of Calcium -so lot of calcium going in
Where are calcium stores found in the cell?
-calcium stores are found everywhere in the dendritic tree, up into the spine, unlocked by PLC
What are the effects of NMDA stimulation?
- is the most important -the first thing Ca encounters when go through NMDA is CaCAM Kinase II
- Calcium entry via NMDA receptors …combined with….
- Calcium release from intracellular stores
- Calcium entry via VACCs, as at all synapses …leads to…
- Activation of CaCam Kinase II (by Ca) 5. Activation of PKA and PKC (by Ca and DAG)
- is the most important -the first thing Ca encounters when go through NMDA is CaCAM Kinase II
What is the Ca/calmodulin protein kinase II?
- The most abundant signalling protein in the PSD is the Ca/calmodulin protein kinase II (CaCamKII)
- It is actually bound to the tail of the NMDA receptor - the first target seen by incoming Ca++
- It may phosphorylate AMPA receptors (increasing their conductance)
- It may also phosphorylate PSD-95 (receptor clustering protein) and cause a greater clustering of AMPA receptors
- It is necessary for structural synaptic plasticity
- the formation of new active zones
- it is a kinase
- it increases the size of depolarisation per glutamate release as more AMPA receptors in the postsynaptic density
- in conjunction with NMDA and other calcium is at the heart of strengthening synapses
- needed for long term memory formation
- if block NMDA no long term memory
- this is the early phase of LTP
- the structural changes where get more active zones, this is the late phase LTP
What are the calcium activated enzymes in dendrites?
- CaM kinase II
- Nitric oxide synthase
- Phospholipase A2 (→ arachidonic acid)
- Calmodulin (→ adenylate cyclase)
- Protein kinase C
- Calpain
What is the retrograde signaling and the messengers responsible?
- everything initiated post synaptically
- there is a pre synaptic component of LTP
- so a retrograde signal must be present, so must go to presynaptic bouton
- these are the candidates: arachidonic acid, nitric oxide, and carbon monoxide
- must be non polar so can cross the membrane
• arachidonic acid
• nitric oxide
• carbon monoxide
What is the presynaptic mechanism of LTP expression?
-not very well understood
• Something that makes transmitter release more reliable. Requires a retrograde signal, probably generated as a result of postsynaptic calcium
Candidates: • AA • NO • CO • O2
• Cannabinoids (adamantane, for example)
What is the associatity/cooperativity feature of associative LTP?
- we want to strengthen a weak input, for that to happen it must be paired with a strong input
- strong inputs close to the cell body, weak usually further away from the cell body
- if fire together then the weak and strong inputs will both strengthen
- so the weak input can be made strong (this is what happens in the dog of pavlov)
• For weak inputs to be potentiated they must be paired with strong inputs.
What are the strong CNS synapses?
-CNS SYNAPSES THAT CONTAIN MULTIPLE ACTIVE ZONES
• Best known example is the mossy fibre synapse in the hippocampus: 10 – 40 active zones
- strong as close to the cell body and have many active zones
- if can pair a weak signal with this it will become stronger
WHY IS THE MOSSY FIBER SYNAPSE “STRONGER”?
- more current flows into the dendrite
- the synapses are located close to the cell body Both factors contribute to greater depolarisation of the neuron
- mossy fibre is the DG to CA3 -the strong connection
How does the classical conditioning work?
show food and salivate, ring bell and nothing
- then pair and eventually will salivate at hearing of the bell
- this pairing neuronally happens via pairing of the A and B neurons
- connection of auditory and visual, connect on neuron X
- eventually will become stronger (as the food will be the strong and the bell weak but eventually bell will be strong)
