Short term Plasicity + Long term Plasticity

Question 1

Synaptic plasticity (2)

what + divided into

Answer 1

• Changes in synaptic efficacy can occur on the range from milliseconds to over the full life time of the organism.
• Divided into two categories: Short term and Long term

We can take the size of our EPSP and strengthen it (make it larger) or weaken it.

Question 2

Whaty dictates the size of quatumn and why?

Answer 2

The number of receptors in the post synaptic membrane dictate size of quantumn. A single vessicle in synaptic cleft, 2K NT and only 20 receptors. Increase from 2K to 15K of NT makes no difference, still going to saturate the receptor.

Question 3

How can synaptic strength change (4)?

conferred by + which is by

Answer 3

Changes in synaptic efficacy are conferred by presynaptic changes in “n” or “p” or by postsynaptic change in “q”
By increasing or decreasing:
- The number of release sites (# of synapse)
- The probability of transmitter release (NMJ is high and fast probability same with brain stem in calyces of Held)
- The number or properties of postsynaptic ligand-gated receptors + how well they work

Question 4

Short term plasticity: Going up (2)

Answer 4

1. Short-term facillitation (presynaptic Ca2+)
2. Post-tectanic potentiation (presynaptic Ca2+)

Question 5

Short-term plasticity: Going down (4)

Answer 5

• Short term depression (vessicle depletion)
• Presynaptic metabotropic receptors DSI and DSE
• Ca2+ channel inactivation
• Postsynaptic receptor desensitization

Question 6

Calcium is cruicial because:

Answer 6

You have to have calcium in the ECM when VG-Ca2+ open. Ca2- will rush in nerve terminal and Ca2+ is important for vessicle fusion.

Question 7

This shows that the amount of Ca2+ makes a huge difference but short term plasiticity there are :

Answer 7

temporal effects of Ca2+ entry and clearance that are important too.

Question 8

Short term presenyaptic facilitation: Paired pulse facilitation (3)

Procedure + what occurs + weaken?

Answer 8

• Two evoked EPSCs in quick sucesssion: record from neuron, stimulating electrode zapping axon comming into that neuron. Evoke, get NT release and current (A), stimulate again and you get even bigger current (B). A and B are exact stimulations you are not doing anything but change time and B change alot.
• Upon the first presynaptic action potential, Ca2+ enters the nerve terminal and causes a small amount of NT release. Upon the second stimulation (if it occurs with little time delay) presynaptic Ca2+ accumulates causing greater amounts of NT release.
• As the time interval increases between the 1st and 2nd presynaptic stimulation, facilitation becomes less apparant as Ca2+ is no longer accumulating.

Question 9

Second current is bigger because of:

Answer 9

Synaptic facilitation. Ca2+ is summating on presynaptic terminal so there is an increase cance of more NT release.

Question 10

Facilitation usually occurs at synapses where:

Answer 10

release probability is initially low.

Question 11

B:A ration when you make PPF time short and long:

Answer 11

Making time between the 2 short: B:A is >1
as you increase the time interval facilitation effect almost gone so B:A approach 1.

Question 12

Post-tetanic potentiation (2)

What + graph

Answer 12

• Residual Ca2+ in the presynaptoc terminal caused by high frequency firing leads to short term enhancement of synaptic transmission. Similar to short term facilitation, presynaptic Ca2+ accumulation is the cause.
• When you tetanize it, you drive Ca2+ into the terminal and even when you stop and go back to normal, the current is still big before decreasing. This is necause it takes time for Ca2+ to be pumped out.

Question 13

Short term synaptic depression occur at:

Answer 13

• synapses that are already high probability release. AP invade terminal, likely to get vessicle fusion.

Question 14

How does vessicle pools in the presynaptic terminal contribute to presynaptic depression (2)?

Background on system + contribution

Answer 14

• There is readily-releasable pool (5-8 vessicles) where the vessicles are docked and ready to release however, only 1 vessicle release at a time even at high probability release. When Ca2+ comes in only 1 go even if you have 5 zippered and docked.

Then you have the reserve pool (17-20 vessicles) where vessicles move dynamically to be zippered in active zone as vesicles are fusing.

Then we have the resting pool (180 vessicles) that help replenish reserve pool.

• Vessicles are always moving into active zone. The number of vessicles in the readily releasable pool and how quickly the pool can be refilled are important variables for short term plasticity.

Question 15

Short term presynaptic depression (paired pulse depression)

What occurs

Answer 15

• Upon the first presynaptic action potential, Ca2+ enters the nerve terminal and causes a large amount of NT release. Upon the second stimulation (if it occurs with little time delay) tehre are not enough vessicles in the readily releasable pool for an equally large amount of transmitter release; thus it will be smaller or depressed. As the time interval increases between the first and second presynaptic stimulation, the depression becomes less apparant as there is enough time for the readily releasble pool to be replenished.

Question 16

Depression usually occurs at synapses where:

Answer 16

release probability is initially high

Question 17

Paired Pulse ration: Increase in presynaptic efficacy (3)

ratio. + mesp + graph

Answer 17

• See a decrease in paired pulse ratio
• See an increase in miniature frequency similar amplitude
• Originally, B and A same size but after treatment, there is an increase on first stimulation on presynaptic terminal and increase presynaptic release. First current is bigger.

Question 18

Paired Pulse ration: Decrease in presynaptic efficacy (4)

ratio + mesp + more likely to see + graph

Answer 18

• See an increase in paired pulse ration (B/A). Second one bigger so facilitation
• See an decrease in miniture frequency but quantal size/amplitude no change
• More likely to see short term faciliytation

Question 19

Paired Pulse ration: Decrease in postsynaptic efficacy (3)

example where this can happen + ratio + MEPSP + amplitude + graph

Answer 19

• Dephosphorylate AMPA so pass less Na+
• No change in paired pulse ratio (B/A)
• No change in miniture frequency
• See amplitude decrease in all current (include EPSP and MEPSP)
• After treatment, current get smaller

Question 20

Paired Pulse ration: Increase in postsynaptic efficacy (3)

Ratio + MEPSP + graph

Answer 20

• No change in paired pulse ratio (B/A)
• No change in miniature frequency (terminal is not releasing more spont. event) but quantal size got bigger
• See amplitude increase in all currents

Question 21

In Paired pulse ratio, amplitude is governed by:

Answer 21

Postsynaptic change

Question 22

In Paired pulse ratio, frequency of miniature events is governed by:

Answer 22

presynaptic release probability

Question 23

Endocannabinoid signalling (3)

type in body + applies to what + mechanism of action

Answer 23

• The system is endogenous (intrinsic) to the brain, meaning it is naturally produced.
• Both excitatory (glutamatergic) and inhibitory (GABAergic) synapses use this system.
• It works as a retrograde signaling system, meaning it travels backward from the postsynaptic neuron to the presynaptic terminal to quiet things down and suppress GABA and glutamate presynaptic release. Calcium influx or mGluR activation can both trigger 2-AG production in the postsynaptic neuron. When the postsynaptic neuron depolarizes (gets excited), voltage-gated calcium (Ca²⁺) channels open. This allows Ca²⁺ ions to flow into the neuron, increasing intracellular calcium levels. High calcium levels stimulate enzymes (like PLCβ and DGLα) to produce 2-AG, which is then released to act on presynaptic CB1 receptors. Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors (GPCRs) that respond to glutamate, an excitatory neurotransmitter. When glutamate binds to mGluRs, it activates a signaling cascade involving Gq proteins, phospholipase C-beta (PLCβ), and diacylglycerol (DAG). This leads to the synthesis of 2-AG, which then acts as a retrograde messenger to suppress presynaptic neurotransmitter release. 2-AG diffuses to the presynaptic neuron and binds to CB1 receptors (cannabinoid receptor type 1).
• This binding sets off a G-proteincascade that inhibits VG-Ca2+ channels and increase opening of K+ channel for eflux and hyperpolarization.

In GABAergic synapses, it reduces GABA release (Short-Term Depression, DSI).
In Glutamatergic synapses, it reduces glutamate release (Short-Term Depression, DSE).
This results in less neurotransmitter release, effectively quieting down overactive synapses.

Question 24

Endocannabinoid depressive mechanism of action:

Answer 24

Presynaptic CB1 activation inhibits adenylate cyclase, decreases cAMP, and reduces calcium influx (inhibit VG-Ca2+ channel) and can increase potassium efflux in the postsynaptic side to hyperpolarize and quiet down the cell. This suppresses neurotransmitter release, modulating synaptic activity.

Question 25

The effects of endocannabinoid signaling on inhibitory postsynaptic currents (IPSCs): Explain Part A

Answer 25

Depolarization (depo.) of the postsynaptic cell (marked by an arrow) leads to a decrease in IPSC amplitude, indicating that inhibitory signaling is reduced. WIN55,212-2 (WIN) is a CB1 receptor agonist, which activates CB1 receptors and further reduces IPSC amplitude, suggesting a presynaptic mechanism. When SR141716A (SR14, a CB1 antagonist) is applied, IPSC amplitude increases again, confirming that CB1 activation suppresses synaptic transmission.

Question 26

The effects of endocannabinoid signaling on inhibitory postsynaptic currents (IPSCs): Explain Part B

Answer 26

In control the paired-pulse ratio B is slightly smaller then A meaning it is a slight depressing synapse but when you put in WIN (activates CB1 receptor) the current gets really small but B is much bigger then A. It is now a facilitating synapase by depressing presynaptic release probability so much. B:A ratio change indicates decrease in presynaptic efficacy, B>A

Question 27

Santiago Ramon y Cajal

Answer 27

- The synapse change for long term memory. Counted neyrons and realized that once you reach a certain age, number of neuron doesnt change,

Question 28

Donald Hebb

Answer 28

When cells communicated to eachother over and over again, A and B gets more efficient. Some growth or metabolic change must be happening.

Question 29

Long term potentiation

Answer 29

A long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronousy. It is considered to be one of the major cellular mechanisms underlying learning and memory from classical conditioning to complex cognition.

Question 30

Long term depression

Answer 30

A long lasting attenuation in signal transmission between two neurons. LTD might be important for the clearing of old memory traces and to keep neurons from synaptic strength saturation or run away excitation.

Question 31

For long term changes (potentiation and depolarization) key mechanism is to:

Answer 31

Change number of receptor to change quantal size

Question 32

explain the volatge graph for NMDA receptors:

Answer 32

- No current at very negative voltages because Mg²⁺ blocks the channel. - Depolarization is necessary to remove the Mg²⁺ block, allowing ion flow. - Reversal Potential (~0 mV): At this voltage, current switches from inward (negative) to outward (positive). - 0 mM Mg²⁺ Condition (Gray Curve): Without Mg²⁺, NMDA receptors behave like AMPA receptors, allowing ion flow regardless of voltage. - Linear I-V relationship, meaning ion flow is not blocked at negative potentials.

Question 33

Conventional methods for achieving LTP and LTD:

Answer 33

LTP: Short bursts of high frequency stimulation combined with postsynaptic depolarization to 0mv LTD: Low frequency stimulation with postsynaptic depolarization to -40mv.

Question 34

Explain the 3 graphs:

Answer 34

Panel A (left graph): Shows synaptic responses over time (EPSCs, or excitatory postsynaptic currents evoked every 30 sec). Black circles at A is normal control condition. After a stimulus (~10 min mark) do a LTP protocol: High freq. stimulation + depol post stnaptic, synaptic responses double in size, showing LTP at B. White circles (NMDA antagonist applied): No increase in response, meaning no LTP. Panel B: Shows the increase in current for LTP Panel C: When APV/AP5 is used: NMDA receptor antagonists (APV or AP5) compete with glutamate at the binding site, preventing channel opening and calcium influx—a critical step for LTP induction. When NMDA is blocked → No LTP.

Question 35

Properties of LTD and LTP

Answer 35

Question 36

LTP or LTD can be induced when you pair presynaptic stimulation with post synaptic depolarization using specific protocols. LTP requires greater -------- and a greater ----- compared to LTD. LTD is still ------- though. Both extracellular field recordings and intracellular whole-cell recordings are used to examine LTP and LTD. Extracellular recordings assess a population of synapses. Intracellular recordings assess synapses on a single neuron.

Answer 36

- NMDA receptor activation - increase in intracellular Ca2+ concentration - Ca2+ dependent

Question 37

In LTP, AMPA receptors are ------. In LTD, AMPA receptors are -----.

Answer 37

- recruited to the post synapse - removed ## Footnote LTP (synaptic strengthening) → More AMPA receptors are added to the postsynaptic membrane, making the synapse stronger. LTD (synaptic weakening) → AMPA receptors are removed, reducing synaptic strength.

Question 38

The majority of AMPA receptors incorporated into synapses during LTP is from (2): Removal in LTD:

Answer 38

lateral diffusion of spine surface receptors containing GluR1 and 2 AMPAR subunits. Following synaptic potentiation, AMPA receptors contained in intracellular pools containing GluR1 and 2 subunits are driven to the surface primarily on dendrites. Insertion (LTP) happens through two mechanisms: Lateral diffusion → AMPARs already present on the cell surface move into the synapse. Exocytosis → AMPARs stored inside the cell are delivered to the membrane. Removal (LTD) happens through endocytosis, where AMPARs are taken back into the cell

Question 39

The role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in long-term potentiation (LTP):

Answer 39

- When intracellular Ca2+ levels rise, Ca2+/calmodulin binds to CaMKII. - This binding leads to the autophosphorylation of CaMKII subunits, resulting in persistent activation of the kinase. - This persistent activation is crucial for LTP, as CaMKII plays a role in strengthening synapses (enables ampa recept. to lock in at synapse). - If the Ca2+ signal is weak or short-lived, phosphatases (blue squares in the diagram) dephosphorylate CaMKII, inactivating it. This ensures that only strong, meaningful stimuli lead to synaptic strengthening, preventing unnecessary or excessive plasticity.

Question 40

How Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the incorporation of AMPA receptors at synapses during long-term potentiation (LTP) (3):

Answer 40

- When intracellular Ca2+ levels rise, CaMKII is activated and phosphorylates AMPA receptors that are already at the synapse. This increases their conductance, enhancing synaptic strength. - CaMKII binds to the NMDA receptor complex, helping to stabilize additional AMPA receptor anchoring sites. This structural organization allows more AMPA receptors to be recruited. - CaMKII facilitates the trafficking of AMPA receptors from intracellular vesicles to the synaptic membrane. New AMPA receptors are inserted into existing or newly formed anchoring sites, increasing synaptic strength. ## Footnote CaMKII acts as a molecular scaffold that enhances synaptic transmission by: Phosphorylating AMPA receptors. Organizing anchoring sites for AMPA receptors. Promoting AMPA receptor insertion into the synaptic membrane. This process is crucial for synaptic plasticity and memory formation during LTP.

Question 41

What makes LTP long term is:

Answer 41

protein synthesis (you need to make more PSD95, CAMKII, AMPA). When glutamate is released into the synapse, it activates NMDA receptors (NMDARs), leading to an influx of calcium ions (Ca²⁺) into the postsynaptic neuron. Calcium-Calmodulin Pathway: Calcium binds to calmodulin, forming a complex that activates CaMK (Calcium-Calmodulin-Dependent Kinases, specifically CaMK I, II, and IV). CaMKs phosphorylate and activate CREB (cAMP Response Element-Binding Protein), a key transcription factor. Once phosphorylated, CREB binds to DNA at specific sites (CRE elements) and recruits coactivators like CBP (CREB-binding protein). This leads to the transcription of genes such as c-fos and BDNF (Brain-Derived Neurotrophic Factor), which are essential for synaptic plasticity and memory formation. The synthesis of new proteins, triggered by CREB-mediated gene transcription, strengthens synaptic connections. This molecular mechanism is what allows LTP to last for hours to days, contributing to long-term memory formation. Other pathways can also activate CREB such as Gs-signaling or tyrosine kinase receptors for growth factors etc.

Question 42

Lower amounts of Ca2+ entry through NMDA receptors activates protein phosphatases that cause -----.

Answer 42

- dephosphorylation and the removal of AMPA receptors from the postsynapse for LTD

Question 43

PSD95

Answer 43

Structural protein physically link and interact with NMDA in post synaptic density

Question 44

If you inhibit CREB or take out process what will happen?

Answer 44

Prevent animal from learning/memory

Question 45

LTP and LTD are accompanied by structural changes of the post and presynapse explain:

Answer 45

- Synapses getting strengthened due to multiple synapses will get bigger (post/pre) and more vessicles at presynapse and more post synaptic receptor so the density enlarge.

Question 46

Explain the mouse retina lesion experiment (2): | what + results

Answer 46

- Under anetheisa, you damage the retina and cells that go from the retina to the hypothalamus cannot send info so visual cortex starts to remodel. - Unilateral retinal lesion does not change overal spine density in the visual cortex but there is a dramatcially loss of previously persistent spines and greater gains in new persistent spines after lesion compared to controls