Short term Plasicity + Long term Plasticity Flashcards
Synaptic plasticity (2)
what + divided into
- 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.
Whaty dictates the size of quatumn and why?
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.
How can synaptic strength change (4)?
conferred by + which is by
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
Short term plasticity: Going up (2)
- Short-term facillitation (presynaptic Ca2+)
- Post-tectanic potentiation (presynaptic Ca2+)
Short-term plasticity: Going down (4)
- Short term depression (vessicle depletion)
- Presynaptic metabotropic receptors DSI and DSE
- Ca2+ channel inactivation
- Postsynaptic receptor desensitization
Calcium is cruicial because:
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.
This shows that the amount of Ca2+ makes a huge difference but short term plasiticity there are :
temporal effects of Ca2+ entry and clearance that are important too.
Short term presenyaptic facilitation: Paired pulse facilitation (3)
Procedure + what occurs + weaken?
- 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.
Second current is bigger because of:
Synaptic facilitation. Ca2+ is summating on presynaptic terminal so there is an increase cance of more NT release.
Facilitation usually occurs at synapses where:
release probability is initially low.
B:A ration when you make PPF time short and long:
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.
Post-tetanic potentiation (2)
What + graph
- 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.
Short term synaptic depression occur at:
- synapses that are already high probability release. AP invade terminal, likely to get vessicle fusion.
How does vessicle pools in the presynaptic terminal contribute to presynaptic depression (2)?
Background on system + contribution
- 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.
Short term presynaptic depression (paired pulse depression)
What occurs
- 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.
Depression usually occurs at synapses where:
release probability is initially high
Paired Pulse ration: Increase in presynaptic efficacy (3)
ratio. + mesp + graph
- 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.
Paired Pulse ration: Decrease in presynaptic efficacy (4)
ratio + mesp + more likely to see + graph
- 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
Paired Pulse ration: Decrease in postsynaptic efficacy (3)
example where this can happen + ratio + MEPSP + amplitude + graph
- 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
Paired Pulse ration: Increase in postsynaptic efficacy (3)
Ratio + MEPSP + graph
- 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
In Paired pulse ratio, amplitude is governed by:
Postsynaptic change
In Paired pulse ratio, frequency of miniature events is governed by:
presynaptic release probability
Endocannabinoid signalling (3)
type in body + applies to what + mechanism of action
- 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.
Endocannabinoid depressive mechanism of action:
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.
The effects of endocannabinoid signaling on inhibitory postsynaptic currents (IPSCs): Explain Part A
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.
The effects of endocannabinoid signaling on inhibitory postsynaptic currents (IPSCs): Explain Part B
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
Santiago Ramon y Cajal
- The synapse change for long term memory. Counted neyrons and realized that once you reach a certain age, number of neuron doesnt change,
Donald Hebb
When cells communicated to eachother over and over again, A and B gets more efficient. Some growth or metabolic change must be happening.
Long term potentiation
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.
Long term depression
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.
For long term changes (potentiation and depolarization) key mechanism is to:
Change number of receptor to change quantal size
explain the volatge graph for NMDA receptors:
- 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.
Conventional methods for achieving LTP and LTD:
LTP: Short bursts of high frequency stimulation combined with postsynaptic depolarization to 0mv
LTD: Low frequency stimulation with postsynaptic depolarization to -40mv.
Explain the 3 graphs:
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.
Properties of LTD and LTP
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.
- NMDA receptor activation
- increase in intracellular Ca2+ concentration
- Ca2+ dependent
In LTP, AMPA receptors are ——. In LTD, AMPA receptors are —–.
- recruited to the post synapse
- removed
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.
The majority of AMPA receptors incorporated into synapses during LTP is from (2):
Removal in LTD:
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
The role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in long-term potentiation (LTP):
- 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.
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):
- 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.
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.
What makes LTP long term is:
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.
Lower amounts of Ca2+ entry through NMDA receptors activates protein phosphatases that cause —–.
- dephosphorylation and the removal of AMPA receptors from the postsynapse for LTD
PSD95
Structural protein physically link and interact with NMDA in post synaptic density
If you inhibit CREB or take out process what will happen?
Prevent animal from learning/memory
LTP and LTD are accompanied by structural changes of the post and presynapse explain:
- 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.
Explain the mouse retina lesion experiment (2):
what + results
- 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
