Chapter 3A: Synaptic Plasticity in Complex Systems, Long-Term Potentiation (LTP) Flashcards
What is the Hebbian synapse?
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”
Do Hebbian synapses exist?
yes
activity dependent enhancement of synaptic transmission
LTP
What did Bliss and Lomo determine about long term potentiation?
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
What is the definition of long-term potentiation?
a long-lasting and activity-dependent increase in synaptic efficacy
synaptic facilitation
same inputs yields a bigger output
What is involved in the induction of long-term potentiation?
LTP due to coincidental activity in pre- and post-synaptic neurons
Hebbian mechanism
What is the presynaptic activity required in the induction of long-term potentiation?
neurotransmitter (glutamate) release
What is the postsynaptic activity required in the induction of long-term potentiation?
“threshold” depolarization
example: spiking
How is co-operativity a property of long-term potentiation?
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
How is associativity a property of long-term potentiation?
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
How is specificty a property of long-term potentiation?
LTP is expressed only in active (not inactive) synapses
LTP induced in an independent pathway does not spill over to other unstimulated pathways
What is the threshold for LTP?
strong activation of inputs is more likely to evoke LTP
simultaneous activation of many inputs
strong activation of single input
Why is temporal contiguity important to LTP?
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
Why is LTP only exhibited in active synapses?
supra-threshold stimulation to a given pathway enhances the response to ONLY that pathway
What is the main mechanism of LTP?
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
How does the release of glutamate onto NMDA receptors cause the activation of second messenger systems?
post synaptic: increase in receptor responsiveness
post synaptic: increase in receptor numbers
pre synaptic: increase neurotransmitter release
anatomical effects: increased synaptic contacts
Why is the NMDA receptor critical to LTP?
blockade eliminates induction of LTP
NMDA double gating provides LTP with the properties of specificity, cooperativity, and associativity
How is the NMDA receptor double gated?
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)
What is the relationship between Ca2+ and LTP?
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
Increases in intracellular Ca2+ activates which protein kinases?
CaMKII
PKC
MAPK
PKA and tyrosine kinase
What is the function of CAMKII in LTP?
activated by LTP-inducing stimuli
activation induces LTP
inhibition blocks LTP
What is the function of PKC in LTP?
activated by LTP-inducing stimuli
activation induces LTP
inhibition blocks LTP
What is the function of MAPK in LTP?
activated by phosphorylation processes during LTP or Ca2+ directly
inhibition blocks gene expression necessary for late LTP
What is the function of PKA and tyrosine kinase in LTP?
specific for strong patterned activity
EC-DG synapse specific
What is the time course of LTP?
LTP has been shown to last days and even weeks
What is the early - induction phase of LTP?
NMDA receptor activation and calcium dependence
What is the medium - expression phase of LTP?
changes to receptors and release machinery
local protein synthesis
What is the late - maintenance phase of LTP?
genomic involvement, transcription dependent
anatomical changes?
What is the definition of long-term depression?
a long-lasting and activity-dependent decrease in synaptic efficacy
synaptic depression
same input yields a smaller output
What does presynaptic activity without postsynaptic activity have to do with LTD?
weak, low frequency repetitive stimulation of input fibers alone
explicit unpairing of weak stimulation and strong stimulation of input fibres (weak input shows LTD)
What does postsynaptic activity without presynaptic activity have to do with LTD?
strong, low frequency repetitive depolarization of postsynaptic cell alone
explicit unpairing of postsynaptic cell depolarization with weak stimulation of input fibres
What is the mechanism of LTD?
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)
What is the purpose the mechanisms of LTD?
desaturation of synapses
contrast effects between potentiated and unpotentiated synapses
How are LTP and LTD generalized brain phenomena?
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
What are the similarities of LTP to learning and memory?
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)
What would be true if LTP is a neural analogue of learning and memory?
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
What are some questions about the correlation between LTP and learning/memory?
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)
What are some questions about the perturbation between LTP and learning/memory?
does blocking LTP block learning and memory?
does inducing LTP by artificial means interfere with learning and memory?
Is the ability to induce or sustain LTP correlated with learning and memory?
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
Do the changes inherent in behavioral learning and memory induce LTP-like changes in the brain (behavioral LTP)?
“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
What is the behavioral LTP experiment involving conditioned fear and the amygdala?
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
What was the behavioral LTP experiment involving motor learning?
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
What was the behavioral LTP experiment involving enriched environments?
condition: rats housed in enriched environments
test: amplitude of hippocampal evoked potentials
result: bigger potentials in enriched rats
Do alterations in the ability to induce or sustain LTP also alter learning and memory?
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
Does behavioral learning and memory alter the ability of circuits to express LTP and vice versa?
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
What was the Morris water maze experiment involving hippocampal LTP and spatial memory?
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)
What was the place cell experiment involving hippocampal LTP and spatial memory?
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)
What are some examples of universal cellular and molecular mechanisms?
electrical events
2nd messenger systems
protein kinases
protein phosphorylation
gene expression
maintained electrophysiological changes
