Chapter 3A: Synaptic Plasticity in Complex Systems, Long-Term Potentiation (LTP)

Question 1

What is the Hebbian synapse?

Answer 1

based upon simple associative learning & memory principles, Donald Hebb came up with a theoretical mechanism of synaptic plasticity involving activity-dependent coincidence

“when an axon of cell A excites cell C and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency in one or both cells so that A’s efficiency as one of the cells firing C is increased”

Question 2

Do Hebbian synapses exist?

Answer 2

yes
activity dependent enhancement of synaptic transmission
LTP

Question 3

What did Bliss and Lomo determine about long term potentiation?

Answer 3

study of the physiology of synaptic transmission in the hippocampus

high frequency stimulation of a particular fibre pathway produced a long-lasting physiological facilitation of its efficacy

called long-term potentiation (LTP)

immediately labeled as a potential model for the synaptic plasticity assumed to be involved in memory

Question 4

What is the definition of long-term potentiation?

Answer 4

a long-lasting and activity-dependent increase in synaptic efficacy

synaptic facilitation

same inputs yields a bigger output

Question 5

What is involved in the induction of long-term potentiation?

Answer 5

LTP due to coincidental activity in pre- and post-synaptic neurons

Hebbian mechanism

Question 6

What is the presynaptic activity required in the induction of long-term potentiation?

Answer 6

neurotransmitter (glutamate) release

Question 7

What is the postsynaptic activity required in the induction of long-term potentiation?

Answer 7

“threshold” depolarization

example: spiking

Question 8

How is co-operativity a property of long-term potentiation?

Answer 8

LTP exhibits a threshold, that is it requires a given strength to stimulate

need to have something happen post-synaptically at great strength

probability of evoking LTP increases with the strength of stimulation and an increase in the number of fibres recruited during the stimulation

Question 9

How is associativity a property of long-term potentiation?

Answer 9

LTP can be evoked by paired (coincidental) stimulation of two different inputs

by simultaneously activating two different pathways to the same target, one weakly and the other strongly, LTP can be induced in the weakly stimulated pathway

Question 10

How is specificty a property of long-term potentiation?

Answer 10

LTP is expressed only in active (not inactive) synapses

LTP induced in an independent pathway does not spill over to other unstimulated pathways

Question 11

What is the threshold for LTP?

Answer 11

strong activation of inputs is more likely to evoke LTP

simultaneous activation of many inputs
strong activation of single input

Question 12

Why is temporal contiguity important to LTP?

Answer 12

pairing independent weak with strong stimuli

induces LTP in weak pathway
weak pathway sub-threshold
strong pathway supra-threshold

similar principle to cooperativity but non-anatomical overlap

Question 13

Why is LTP only exhibited in active synapses?

Answer 13

supra-threshold stimulation to a given pathway enhances the response to ONLY that pathway

Question 14

What is the main mechanism of LTP?

Answer 14

threshold stimuli release large amounts of glutamate onto two types of receptors:
AMPA receptors (classic ionotropic neurotransmission)
NMDA receptors (conditioned ionotropic neurotransmission, Ca2+ entry)

result: larger response recorded for same input

Question 15

How does the release of glutamate onto NMDA receptors cause the activation of second messenger systems?

Answer 15

post synaptic: increase in receptor responsiveness
post synaptic: increase in receptor numbers
pre synaptic: increase neurotransmitter release

anatomical effects: increased synaptic contacts

Question 16

Why is the NMDA receptor critical to LTP?

Answer 16

blockade eliminates induction of LTP

NMDA double gating provides LTP with the properties of specificity, cooperativity, and associativity

Question 17

How is the NMDA receptor double gated?

Answer 17

double-gated – coincidence detector

ligand dependent (requires binding of neurotransmitter) as well as voltage-dependent (requires depolarization to remove Mg2+ block of channel pore)

activation requires both elements: glutamate binding and postsynaptic depolarization (via AMPA receptor activation and temporal and spatial summation of EPSPs)

Question 18

What is the relationship between Ca2+ and LTP?

Answer 18

NMDA receptor channel permeable to Ca2+: depolarizes postsynaptic neuron, acts as second messenger

postsynaptic Ca2+ increases critical for LTP: Ca2+ chelators block LTP induction, release of caged Ca2+ induces LTP

Question 19

Increases in intracellular Ca2+ activates which protein kinases?

Answer 19

CaMKII
PKC
MAPK
PKA and tyrosine kinase

Question 20

What is the function of CAMKII in LTP?

Answer 20

activated by LTP-inducing stimuli

activation induces LTP

inhibition blocks LTP

Question 21

What is the function of PKC in LTP?

Answer 21

activated by LTP-inducing stimuli

activation induces LTP

inhibition blocks LTP

Question 22

What is the function of MAPK in LTP?

Answer 22

activated by phosphorylation processes during LTP or Ca2+ directly

inhibition blocks gene expression necessary for late LTP

Question 23

What is the function of PKA and tyrosine kinase in LTP?

Answer 23

specific for strong patterned activity

EC-DG synapse specific

Question 24

What is the time course of LTP?

Answer 24

LTP has been shown to last days and even weeks

Question 25

What is the early - induction phase of LTP?

Answer 25

NMDA receptor activation and calcium dependence

Question 26

What is the medium - expression phase of LTP?

Answer 26

changes to receptors and release machinery local protein synthesis

Question 27

What is the late - maintenance phase of LTP?

Answer 27

genomic involvement, transcription dependent anatomical changes?

Question 28

What is the definition of long-term depression?

Answer 28

a long-lasting and activity-dependent decrease in synaptic efficacy synaptic depression same input yields a smaller output

Question 29

What does presynaptic activity without postsynaptic activity have to do with LTD?

Answer 29

weak, low frequency repetitive stimulation of input fibers alone explicit unpairing of weak stimulation and strong stimulation of input fibres (weak input shows LTD)

Question 30

What does postsynaptic activity without presynaptic activity have to do with LTD?

Answer 30

strong, low frequency repetitive depolarization of postsynaptic cell alone explicit unpairing of postsynaptic cell depolarization with weak stimulation of input fibres

Question 31

What is the mechanism of LTD?

Answer 31

likely both pre and post-synaptic elements: decrease in neurotransmitter release, decrease in receptor numbers due to a weak (subthreshold for LTP) elevation of postsynaptic Ca2+: activation of phosphatases (reduction of kinase activity)

Question 32

What is the purpose the mechanisms of LTD?

Answer 32

desaturation of synapses contrast effects between potentiated and unpotentiated synapses

Question 33

How are LTP and LTD generalized brain phenomena?

Answer 33

although LTP and LTD were discovered and extensively studied in the hippocampus, both phenomena have been described in many other brain areas including: neocortex cerebellum subcortical structures; e.g. amygdala brainstem spinal cord

Question 34

What are the similarities of LTP to learning and memory?

Answer 34

LTP: activity-dependent, cooperative, associative, input specific, time course (rapid induction, long duration, temporal phases: early and late) Learning and memory: experience-dependent, attention-dependent, associative, stimulus specific, time course (rapid induction, long duration, temporal phases: short-term and long-term)

Question 35

What would be true if LTP is a neural analogue of learning and memory?

Answer 35

learning should elicit an LTP-like change in the brain disruption or blockade of LTP should disrupt or prevent learning but should not interfere with previous memories artificial LTP should interfere with previous memories artificial LTP should interfere with normal learning or induce false memories, learning should also "saturate" LTP reversal of LTP should erase previous memories

Question 36

What are some questions about the correlation between LTP and learning/memory?

Answer 36

does the ability to induce LTP relate to the ability to learn? (developmental or genetic modifications in LTP) does learning "induce" an LTP like modification? (behavioral LTP)

Question 37

What are some questions about the perturbation between LTP and learning/memory?

Answer 37

does blocking LTP block learning and memory? does inducing LTP by artificial means interfere with learning and memory?

Question 38

Is the ability to induce or sustain LTP correlated with learning and memory?

Answer 38

older rats have poor hippocampal LTP and show poor spatial memory spatial memory in developing rats emerges at the same time that the hippocampus is functional and capable of LTP different inbred strains of mice show differences in LTP problem: not perfectly correlated with learning and memory performance

Question 39

Do the changes inherent in behavioral learning and memory induce LTP-like changes in the brain (behavioral LTP)?

Answer 39

"enriched" animals display LTP-like enhancements fear conditioning commensurate with LTP-like enhancement of thalamic input to amygdala motor learning yields differences in LTP abilities of motor cortex

Question 40

What is the behavioral LTP experiment involving conditioned fear and the amygdala?

Answer 40

condition: pair buzzer with electric shock, rats freeze when exposed to buzzer alone (fear response) method: measure evoked potential in amygdala to thalamic input result: LTP induced in pathway expressed as bigger potential to electrical AND auditory stimulation, fear learning results in bigger potential to electrical stimulation

Question 41

What was the behavioral LTP experiment involving motor learning?

Answer 41

condition: one hand reaching task method: measure evoked potential in ipsilateral and contralateral motor cortex result: bigger evoked potential in contralateral motor cortex following the training

Question 42

What was the behavioral LTP experiment involving enriched environments?

Answer 42

condition: rats housed in enriched environments test: amplitude of hippocampal evoked potentials result: bigger potentials in enriched rats

Question 43

Do alterations in the ability to induce or sustain LTP also alter learning and memory?

Answer 43

pharmacological, genetic: interfering with the process of LTP generally interferes with learning and memory protein inhibitors differentially interfere with early versus late stages of LTP and memory: parallel elements of induction versus expression in LTP and memory

Question 44

Does behavioral learning and memory alter the ability of circuits to express LTP and vice versa?

Answer 44

in old rats, memory is impaired after the induction of LTP saturation of LTP impairs learning ability LTP like changes in motor cortex after motor learning also affect difficulty in eliciting experimental LTP

Question 45

What was the Morris water maze experiment involving hippocampal LTP and spatial memory?

Answer 45

condition: spatial learning in Morris water maze method: intrahippocampal infusion of AP-5 (block LTP) result: impairments in spatial learning, similar results with genetic modifications of LTP (CaMKII)

Question 46

What was the place cell experiment involving hippocampal LTP and spatial memory?

Answer 46

condition: open field foraging while recording multiple place cells in hippocampus method: genetic modification of LTP (CaMKII) result: place field instability, similar results with pharmacological blockade of LTP (AP-5)

Question 47

What are some examples of universal cellular and molecular mechanisms?

Answer 47

electrical events 2nd messenger systems protein kinases protein phosphorylation gene expression maintained electrophysiological changes