WEEK 4 Flashcards
synaptic plasticity
history-dependent change in synaptic transmission.
1) it can increase or decrease
2) change can be short-lasting (STP, STD) or long-lasting (LTP, LTD)
patient H.M.
suffered from severe epilepsy. doctors lesioned the area of the brain which produces it, which included the hippocampus. though the lesion worked for his epilepsy, it also resulted in severe memory impairment. so it is thought the hippocampus is important for learning and declarative memory.
how to study synaptic plasticity in the hippocampus?
using an electric stimulation electrode, which can evoke APS on axons. it is placed onto Schaffer collaterals to produce APs, which propagate down the axon to ultimately induce neurotransmitter release. you then need a recording electrode to measure synaptic potentials.
different forms of synaptic plasticity
1) short-term potentiation (STP): lasts for about 30 minutes and depends on a high frequency stimulation
2) post-tetanic potentiation (PTP): declines even quicker than STP.
2) long-term potentiation (LTP): occurs after STP has subsided, and can last for several hours and even up to a year if you use electrical stimulation. requires a higher frequency stimulation to be invoked.
3) long-term depression (LTD): stimulation is very low frequency and leads to a depression of synaptic transmission that lasts for a long period of time.
LTP properties
1) it is long-lasting
2) it is input-specific: it is specific to the activated synapses only, and doesn’t affect neighboring synapses.
3) it has the principle of cooperativity: you need a threshold stimulation to induce LTP, so not any signal can produce LTP, only signals of relevance.
4) it has the principle of associativity: applies to LTP at two different synapses. if one synapse undergoes a weak stimulation insufficient to produce LTP, this stimulation can be converted into an LTP inducing stimulation when a neighboring synapse experiences LTP induction.
LTP: receptors
1) AMPARs bind glutamate when they are opened. they then allow sodium ions to flux to the postsynaptic membrane, depolarizing it. they are the main carriers of glutamatergic transmission.
2) NMDARS require both glutamate and depolarization to open. so they require two coinciding events: glutamate release from the presynaptic terminal, and postsynaptic depolarization, as they are blocked by magnesium ions which only unblock them through depolarization. once opened, they allow calcium ions to enter the postsynaptic membrane. these second messengers trigger signaling cascades: calcium binds to calmodulin, which activates kinases, which modify how the synapse works, like phosphorylating AMPARs for better conduction.
ways to enhance synaptic transmission
1) at the postsynapse: NMDARs allowing calcium ions in, which bind to calmodulin, which activates kinases, which modify synapse conductivity, phosphorylating AMPARs and enhancing transmission.
2) at the postsynapse: increasing number of AMPARs through more AMPAR vesicles. there are endosomes in the post synapse that contain AMPARs, and they can be fused with the membrane so you get more AMPARs.
3) there are also AMPARs outside the postsynaptic zone and they can be diffused into the membrane, enhancing density of AMPARs.
4) at the presynapse: you need to get a signal across from the post synapse to the pre synapse to modify and increase presynaptic glutamate release: RETROGRADE SIGNALING
CAMKII and LTP production
calcium calmodulin-dependent kinase II is an enzyme that can increase the density of AMPARs, so seems to be critical for the induction of LTP.
Kandel (late LTP)
L-LTP: these forms of LTP require protein synthesis and gene transcription to be very long-lasting. after the induction of L-LTPs, new proteins need to be synthesized to contribute to its long lasting nature. to get L-LTP, one needs even stronger stimulation: you need 3x as much stimulation to activate gene expression and protein synthesis required for L-LTP.
synaptic tagging (L-LTP)
1) once the signal reaches the nucleus, it results in gene expression, followed by mRNA translation and protein synthesis.
2) these newly synthesized proteins (plasticity related proteins, PRPs) can only be taken up by tetanized synapses - preserving synapse specificity.
3) the strong tetanization induces a molecular change, a so called “tag setting”, that captures PRPs.
4) taking up the PRPs then allows the LTP to be developed into an L-LTP.
this process also has associative properties: if a strong tetanization coincides in time with another synapse with a weaker signal, then the weak tetanized synapse can still induce a tag setting, taking up PRPs so it can develop L-LTP.
LTP maintenance
stimulated synapses have mRNA that encode PKMz. When LTP is induced, in particular L-LTP, PKMz mRNA is translated. we get PKMz protein, a kinase that is active all the time, and that keeps on promoting AMPAR density, maintaining LTP. PKMz is only around a few hours a day, but because it can self-synthesize, the mRNA remains and can be translated further to produce more PKMz proteins. at synapses that maintain LTP, there should be PKMz that is active all the time.
different forms of memory
can be distinguished by:
1) time scale:
- short-term memory
- long-term memory
- working memory
2) brain areas involved:
- hippocampus (declarative memory, for humans + rodents: spatial memory, contextual memory)
- cerebellum
O’Keefe: hippocampus, spatial memory
discovered the importance of the hippocampus in the process of making a spatial map of the environment, a so-called “cognitive map”.
Morris: water maze to study spatial memory
pool with opaque water where there is a resting platform. the animal has to learn to locate the platform using cues in the room. the animal cannot learn this in one attempt, though.
learning phases:
1) the animal will try to climb out of the pool until it has learned that there’s no escape
2) the animal will then explore the environment by swimming around randomly until it bumps into the platform
3) the animal then learns to use the platform as a resting spot
4) the animal will develop a strategy (procedure) to locate the platform, which ultimately leads to spatial learning.
we can test spatial learning by removing the platform from the pool after training and allow the animal to search for it.
passive avoidance task
simpler task to assess hippocampus learning, as it can be learned in a single training trial. a rodent is placed in a light compartment connected to a dark component. rodents like the dark, so naturally it would move towards the dark component. once there, it receives a foot shock. after the training trial, the rodent avoids going into the dark room. this requires the hippocampus.
advantages of a one-trial learning task
1) all animals learn at the same time
2) useful in the study of molecular and cellular processes since all animals learn at the same time
3) more suitable in the study of learning and memory processes in comparison to the water maze due to lack of synchronization in animal behavior
4) easy to distinguish between short term and long term memory since all animals are synchronized
Hebb (1949)
“when an axon of neuron A excites neuron B and repeatedly takes part in firing it, some growth processes or metabolic changes take place in one or both neurons so that A’s efficiency as one of the firing cells of B is increased”
- though LTP follows this principle, it is synaptic transmission that is enhanced, not the firing.
passive avoidance task and LTP: study
electrodes were implanted into area C1 of the hippocampus. there are many electrodes as behavior was used to induce LTP, so maybe only a small set of synapses undergo LTP.
FINDINGS: trained animals show an enhancement of synaptic transmission which seemed to be long-lasting. this was true for 30 mins, 1 hour, 2 hours after training, up to 4 hours. trained rodents showed higher potentiation compared to naive rodents. in fact, no LTP was induced in performance controls (walk-through or shock-only) groups, showing that behavioral training can induce LTP.
CONCLUSION: LTP occurs during memory formation.
maze trial memory probe task with an NMDAR blocker: study
rats were treated with an NMDAR blocker, AP5.
FINDINGS: drug treated rats had a random search, indicating they had no spatial memory, whereas control animals show spatial bias.
CONCLUSION: this indicates that blocking NDMAR impairs spatial learning, suggesting that LTP is important for learning.
CAVEAT: it’s important to note that the drug dose was high, so the animals had some performance abnormalities. furthermore, blocking NMDARs not only blocks LTP, but also blocks LTD.
Tonegawa: region-restricted knockout mice
knocked out an essential NMDAR subunit (GluN1) exclusively in the hippocampus. he succeeded in having a mutant mouse with no expression of GluN1 exclusively in the CA1 region (hippocampus).
knockout mice water maze study
knocking out NMDARs in the CA1 of mice showed impaired spatial learning. knockout mice showed random search, so no spatial memory. these findings are consistent with the pharmacological blockage of NMDARs.
CAMKII-T286A mutants
the autophosphorylation of CAMKII is important for maintaining LTP, therefore there was interest to make a mutation that blocks its autophosphorylation. these animals have severely impaired LTP in the CA1 of the hippocampus.
CONCLUSION: the autophosphorylation of CAMKII at theonine-286 is fundamentally important for LTP induction.
study: mutants showed equal search in all quadrants of the water maze, showing impaired spatial learning. so mutants lack both LTP induction and spatial memory, further strengthening their correlation.
block of LTP maintenance: rotating platform task
ZIP is a peptide that blocks PKMz, important for LTP maintenance. rats are placed on a rotating platform. when rotated towards a particular area, the rats receive a shock. they then learn to avoid going into the area (active avoidance). this requires a few training trials. the memory of it lasted up to 24h in control rats.
FINDINGS: rats injected with ZIP kept going back to the danger zone. so ZIP erased the memory and LTP, showing a strong correlation between LTP and memory maintenance.
3 types of synapses
1) axiodendritic/axiospinal
- axon to dendrite or dendritic spines
- account for the majority of synapses in the brain
- excitatory, inhibitory, and neuromodulatory
2) axiomatic
- axon to cell body
- inhibitory or neuromodulatory
3) axioaxonic
- axon to axon
- controls the amount of info flow on the postsynaptic neuron
postsynaptic density (PSD)
on the dendritic spine head, the postsynaptic density (PSD) contains neurotransmitter receptors which receive the info from the presynaptic neuron and translates these signals into a response in the postsynaptic cell.
dendritic spines: functions
1) they increase the surface area, and thus the potential number of synaptic connections a postsynaptic neuron can make.
2) they can compartmentalize both electrical and chemical signals from the cell. they can filter or amplify signals both by chemical and electrical before even allowing it into the cell, thus influencing the output of the neuron. in order to do this, they have specialized shapes and a vast number of proteins including receptors, adhesion proteins, and scaffold proteins. the rearrangement of F-actin allows spines to take shape and change shape. they also contain organelles responsible for the production of proteins.
spinogenesis (filopodial model)
when the pre and postsynaptic neurons have been established, the dendrite creates a dendritic protrusion, a filopodia, that is very long and very dynamic. filopodia don’t have a discernible head structure and do not contain the proteins necessary to create a synaptic connection, no PSD, or receptors. the filopodia searches for an appropriate synaptic partner (TARGET SELECTION).
