Exam 3: Topic 8 Flashcards
(82 cards)
1
Q
Hebbian plasticity
A
only the synapses that fire together wire together
- combinations of certain inputs will modify the neuron over time when they have the same pattern of activity
- cells with different patterns won’t become strengthened and synapses will be lost
2
Q
what 2 classifications are involved in plasticity?
A
- Post-synaptic: molecules in the postsynaptic cell change first
- Pre-synaptic: molecules in the presynaptic cell change first (less well understood)
- its probably a combination of pre- and post- synaptic plasticity that determines synapse changes
2
Q
what two things are needed for Hebbian plasticity?
A
specificity and associativity
3
Q
because neurons function in networks what happens when you change a molecular function in one cell in the network?
A
it can lead to functional changes in other cells in the network
4
Q
which neural mechanistic changes are well understood? (2)
A
hippocampus LTP and NMDA receptor dependent changes
- This does not necessarily mean the most well studied mechanisms are the most important for the function of the nervous system
5
Q
NMDA receptor dependent
A
whatever the mechanism that initiated the changes, ultimately, there are changes in the NMDA receptor activity
6
Q
what two phenomena happen with post synaptic NMDA receptor changes? (More or less)
A
- LTP via increased AMPA and/or NMDA receptor activity
- LTD via reduced AMPA and/or NMDA receptor activity
7
Q
what happens at the PSD with AMPA and NMDA changes?
A
they have an altered presence in the plasma membrane
8
Q
what molecular things regulate the ligand/voltage gated channel receptor activity relating to NMDA and AMPA? (3)
A
- phosphorylation/dephosphorylation
- Oxidation
- Subunit expression
9
Q
how does LTP work at the CA1/CA3 hippocampal synapse?
A
Baseline EPSP in CA1 is stable over time (-15-0 min) when stimulating low frequency schaffer collaterals but following a brief period of high frequency (tetanic) stimulation to mimic a burst of synaptic activity there is a rapid, high increase in [Ca2+]i for a few minutes
- Strength of EPSP increase ⇒ this increase remains even following the return to baseline stimulation of schaffer collaterals
10
Q
what can happen with mutations/treatments interfering with LTP?
A
it reduces behavioral tests of memory
11
Q
what happens with high frequency stimulation of AMPAR and NMDAR?
A
there is prolonged activation and increased Ca2+ which creates LTP
12
Q
what changes in receptors does LTP cause? (2)
A
- Increased activity of synaptic AMPA receptors
- Additional AMPA receptors are trafficked to the surface membrane
13
Q
what are AMPAR changes due to? What is influenced? (2)
A
activation of CaMKII
1. inserts new AMPA receptors at PSD
2. influences AMPA outside the PSD to migrate closer
14
Q
what is the sequence of steps in a glutamate synapse/postsynaptic cell leading to increased synaptic strength?
A
- glutamate NT is released and this binds to AMPA
- AMPA letting NA+ in the cell allows for an increase in Vm and NMDA receptors become unblocked to allow Ca2+ in
- Ca2+ activates CaMKII so more AMPA is inserted and and PKA is also activated to phosphorylate AMPA and let in positive current
- recycling endosomes allow AMPA to be inserted via synaptotagmins
15
Q
how NMDA a dual sensor?
A
- the Mg2+block of the NMDA receptors means that the receptor only opens at Vm»Vrest
- depolarization by the AMPAR removes the Mg2+ and enables the NMDAR to open - NMDA must bind glutamate
16
Q
what kinds of modulation decrease NMDA current? (3)
A
- cystine can be reduced
- Serine/Threonine can be dephosphorylated
- Tyrosine can be dephosphorylated
- other things are presence of H+ and Zn2+ and polyamides in the channel
17
Q
what kinds of molecules dephosphorylate Ser/Thr? (3)
A
- PP1
- 2A
- 2B/Calcineurin
18
Q
what kinds of modulation increase NMDA current? (3)
A
- cystine oxidized
- Serine and threonine phosphorylated
- tyrosine phosphorylated
- other things are polyamides out of the channel
19
Q
what kinds of molecules phosphorylate Ser/Thr? (3)
A
- PKC
- PKA
- CaMKII
20
Q
what kinds of molecules phosphorylate Tyr? (2)
A
- Src
- Fyn
21
Q
what happens during development where NMDA-R is less inhibited by Mg2+?
A
this means the body is less dependent on AMPA-R for activity
22
Q
what do silent synapses lack?
A
AMPA receptors
- occurs with immature synapses or synapses after LTD only containing NMDA
- you cannot activate the cell when at rest due to some sort of block (Mg2+ block)
- inactive during baseline neurotransmission
- After AMPAR are inserted, these synapses become active with baseline neurotransmision
23
Q
what are AMPA receptors dependent on?
A
CaMKII
- the same synapse can be either potentiated or depressed under certain states
24
depression
weakening of a synapse
25
what happens at CA1 neurons with depression?
baseline EPSP in CA1 neurons is stable over time (0-15 min) when stimulating Schaffer collaterals but following a prolonged period of low frequency (1 Hz) stimulation there is slow, moderate increase in [Ca2+]i for prolonged period and strength of EPSP decreases below baseline
- The decrease remains even following the return to baseline stimulation of Schaffer collaterals
26
how does LTD affect AMPA receptors? (2)
- results in decreased activity of synaptic AMPA receptors
- AMPA receptors are removed from the surface membrane (internalized)
27
what are AMPA changes from LTD due to?
activation of calcium dependent phosphatases (Calcineurin)
28
what happens with low frequency stimulation to glutamate neurons?
leads to a slower increase in Ca2+ and lower amount biased toward activating phosphatases ⇒ removal of AMPA from the membrane
- for high freq stimulation there is a strong activation of AMPA and NMDA which increases calcium fast/large biased toward activating kinases ⇒ insertion of AMPA receptors
29
what is the process of LTD via low frequency stimulation in glutamate neurons?
1. glutamate NT is released
2. this binds to NMDA and AMPA but NMDA will let in Ca2+ and AMPA will let in Na+
3. Ca2+ triggers protein phosphates which will influence clathrin coats to take out AMPA receptors from the plasma membrane
4. AMPA receptors get put into sorting endosomes away from the plasma membrane
30
what are kinases that increase NMDA and AMPA receptor activity?
1. PKC
2. PKA
3. CaMKII
31
what are phosphatases decreasing NMDA and AMPA activity?
calcineurin
32
what enzyme affects voltage gated K+ channels to decrease activity? What does this cause?
PKA
- causes longer AP duration
33
what enzyme affects voltage gated Ca2+ channels to increase activity? What does this cause?
PKA
- causes more synaptic vesicle fusion
34
what happens in wild type cells with alphaCaMKII in the hippocampus?
Baseline stimulation is at a low frequency and baseline is stable
- with a low frequency stimulation (1 Hz) there is a depression measured lasting multiple minutes, hours, days
- The same synapse can be given a high frequency stimulation and there is a strong enhancement of the synapse which decays fast and stays potentiated for minutes, hours, days
35
what happens if we knockout alphaCaMKII in the hippocampus so it is no longer a wild type cell?
- without CaMKII there is an initial depression that comes back almost to baseline within a few minutes
- without CaMKII there is an elimination of LTP where after stimulation the cell almost immediately goes back to baseline again
36
what is the conclusion of stimulation levels for wild type cells?
the same synapse is depressed or potentiated based on the type of stimulus in a wild type cell
37
what is the conclusion of stimulation levels for non wild type cells?
there is a large impact on LTP but smaller impact on LTD where each returns to baseline faster than wild type conditions
38
how does pavlovian fear conditioning work with mice?
they learn to address their associative memory
- At some point there is a mild shock while in a novel environment
- 24 hours later if the mouse is placed back in (even without a stimulation) the mouse will have a freezing response ⇒ because it didn't like the shock
39
what molecular signs do we see in pavlovian fear conditioning?
there is enhanced EPSP firing for the mouse that was shocked after baseline conditions
- there is elevated CaMKII for about 1 week after shocks
- there is a significant difference in the freezing response between wild type mouse conditions and shock conditions
40
what happens if you lesion a mouse hippocampus and shock it?
the animal will not be able to learn to freeze in the box
41
what happens with over expression of CaMKII in learning?
there is an increase in LTP but behaviorally it reduces ability to learn ⇒ the amount of CamKII is too biologically high for the cell to be used to it
42
Novel object recognition
tests recognition memory
43
what occurs for mice in novel object recognition?
the mouse is placed in a chamber with two objects which it will naturally explore for the about the same amount of time ⇒ no bias or preference
- in a new environment, the mouse remembers the old object so it spends less time investigating it but it remembers the new object hasn't been there before so it spends more time with this object
44
what happens to object recognition if you lesion the hippocampus?
there is a strong effect and the mouse wont remember which is old and new so it spends equal amounts of time analyzing both objects again
45
what happens with over expression of NMDA GluN2A subunits?
it decreases LTD and impairs learning
- the wild type mouse will remember it has seen both objects but over long time they forget that they have explored one of the objects previously => There is learning and memory but also active forgetting
- mutant mice have no LTP changes and decreased LTD
46
what do novel object recognition tests and active forgetting tell us about memory?
LTD is also important for memory as well as LTP
47
what are the subcomponents of dendrites? (4)
- Shaft and coming off of that is the neck
- At the end of the neck you have the head
- The head contains the postsynaptic density (PSD)
- An axon from another cell has an active site where it releases NT and binds to the head of the spine at the PSD
48
what are cell adhesion molecules? (3)
1. EphrinB
2. Neuroligin/Neuroexin
3. N-Cadherin/BCatenin
- all 3 types connect the two neuron structures together
49
what are NT receptors in glutamtergic cells? (3)
1. AMPAR
2. NMDAR
3. mGluR ⇒ extrasynaptic (tend to be
on the periphery of the spine itself)
50
scaffolding/anchoring proteins (2)
1. PSD-95 => next to the plasma membrane connecting receptors to inner scaffolding
2. Actin => on the most innermost parts of the head closer to the shaft
51
T/F the presynaptic terminal and the head need to be connected to one another
True
- happens via CAMs where they anchor the cells together
- The scaffolding links to cell adhesion molecules to make sure the structures are stable
52
what protein gives structure to the head of the dendritic spine?
actin => when degraded the spines will disappear
53
what do normal infant dendrites look like compared to non-syndromic infants, fragile X syndrome, and severe intellectual disability in 12 year olds?
normal dendrites have short necks and lots of visibly packed heads close to one another
- for non-syndromic they have longer necks, less volume of heads, and fewer spines
- for fragile X the necks are abnormally long but there is a high volume
- for severely disabled 12 year olds they have long necks and an absence of volume of dendrites (even more than non-syndromic)
54
how can you image dendritic spines in live animals?
You can open the skull up and shave it down ⇒ with less bone tissue you can eventually see through the brain and shine light into it via a microscope
- The dark black structures are vasculature which can be used as landmarks ⇒ they won't change
- you can do a 3D reconstruction through the tissue to see where the dendrites are (X layers)
- Confocal microscopes let you look at each layer so you can see individual dendrites (E and F are same dendrite in the same location 3 days apart)
55
T/F dendrites should have the same spines at the same locations which tells us they are consistent and not changing?
True
56
how does LTP change dendritic spine head plasticity?
At 0 minutes there is no LTP but following LTP the head volume increases and stays increased for an hour+ as more current is coming through the spine head
57
what are the 3 changes that occurs in dendrites with LTP?
- Stimulated spine head gets larger
- Increased AMPA-R current in stimulated spine (via microelectrode)
- Effect is specific for the stimulated spine, does not occur in neighboring spines
58
what happens to the dendritic spine with LTD?
spine gets smaller over time
- Long low frequency stimulus does this
59
where are Ca2+ micro domains located in dendritic spines?
the head itself has lots of calcium vs. less in the shaft
60
how does calcium density change with long vs short necks?
calcium channels are located in the head because in the long neck there is very little calcium in the neck compared to the head vs with the shorter neck there is a lot in the head but more in the neck so the calcium from the head is diffusing into the shorter neck
- with long neck, Ca2+ increase is restricted to the head ⇒ less Ca2+ in the shaft
- with a short neck, Ca2+ diffuses to dendrite shaft
61
what happens when glutamate is released?
binds to AMPA and NMDA receptors, calcium comes in via NMDA, calcium will bind to calmodulin and this activates CaMKII
62
what is the CaMKII response in the dendrite head? (2)
1. it phosphorylates NMDA receptors to make them more efficient so calcium comes through
2. Leads to more AMPA receptors so the cell is more active in response to stimulation
63
what happens to CaMKII responses in people with long necked dendrite spines?
the response is weakened
64
which direction does CaMKII diffuse in the dendrite?
from the shaft out to the head
65
what happens with tatanic stimulation in dendritic spine heads over milliseconds?
short transient increase in Ca2+ in the stimulated spine
66
what happens with titanic stimulation in dendritic spine heads over seconds?
activation of CaMKII that is already in the stimulated spine
67
what happens with tetanic stimulation in dendritic spine heads over minutes?
more CaMKII moves into the stimulated spine
and LTP in the stimulated cell
68
T/F when LTP is induced you get a change pre and post stimulus where the cell becomes more responsive and this also happens in non LTP activated spines?
False this happens in the stimulated cell but does not happen in adjacent spines unaffected by LTP
69
what long term changes occur in neuron morphology with LTP? (2)
1. Number of synaptic spines change ⇒ more or less (increased strength with more synapses)
2. Insertion of more AMPA receptors via calcium and CaMKII (effective synapse)
70
what is the initial phase for LTP?
presynaptic cell releases neurotransmitter to bind to AMPA and NMDA receptors
- Calcium comes in, binds to calmodulin, activation of CaMKII, more AMPA and phosphorylation, etc.
71
what happens in the late phase?
Via adenylyl cyclase the regulatory subunits of PKA to translocate to the nucleus to activate CREB which leads to new synapses and insertion of new synapses including actin growth
72
what happens when a presynaptic cell and a postsynaptic cell are stimulated at the same time with high freq?
you will get spine growth at the site and have more synapses
73
what happens when a presynaptic cell and a postsynaptic cell are stimulated at the same time with low freq?
there is shrinkage instead of growth at the spine as well as a reduction in the amount of spines leading to LTD
74
scaling up
depriving activity where you get an increase in spine density and size of spines
- not being activated enough
75
scaling down
prolonged activity will lead to reduced spine density and or size
- too much activity
76
what are mechanisms of spine growth? (2)
1. LTP
2. scaling up
77
what are biological correlation of spine size and growth? (4)
- spine stabilization
- reduced spine dynamics
- synaptic strengthening
- increased surface of AMPARs
78
what are mechanisms of spine shrinkage? (2)
1. LTD
2. scaling down
79
what are biological correlated of spine size shrinkage? (4)
- spine elimination and or pruning
- increased spine dynamics
- synaptic weakening
- reduced surface AMPARs
80
end card
hehe :)
82
When do NMDA receptors activate?
When Vm >> Vrest
