Lecture 14: Long Lasting Potentiation – Induction and Expression Flashcards
How did Donald Hebb view the brain?
as a set of interconnected cell assemblies (neural circuits) through which there are flows of activity – repeated flows of activity in one set of neurons would strengthen connections (synapses) between them
What is Hebb’s postulate?
when axon of cell A is near enough to excite cell B, and repeatedly and persistently takes part in firing it, some growth process or metabolic changes takes place in one or both cells such that A’s efficiency in firing B is increased
What happens if you increase the efficiency (strength) of synapse that has been active during a particular flow of activity?
that flow will happen more easily in the future
Why does enhancing the strength of a particular synapse in a cell assembly that is active during a particular event (ie. memory) produce memory?
if part of the assembly is activated in the future, the strengthened synapses will enable efficient transmission/replay of the same pattern of activity, even if it is a weaker triggering stimulus
What are the 2 key model systems for understanding long-term synaptic plasticity?
- vertebrate hippocampus
- Aplysia nervous system
Where in the brain would you even look for a memory ‘trace’?
- removal of medial temporal lobes (including hippocampus) caused inability to form new memories
- knowing the hippocampus is involved in memory does not explain how it forms those memories
What were the roadblocks to being able to link Hebb’s ideas to real brain structure?
- knowing what to look for – what is encoded in a memory, and how sparsely it would be spread
- being able to look – hippocampus is in middle of CNS, and it is very seizure prone
What type of circuit does the hippocampus form?
trisynaptic circuit – pass information from one sub-region to the next, then sending it back to the rest of the brain
How many neurons and synapses are there in the hippocampus?
millions of small neurons, thousands of individual synapses each
What are the advantages of Aplysia’s nervous system for doing physiology and molecular biology experiments, compared to vertebrate hippocampus?
- accessible – no skull or BBB
- small – 10,000s of neurons
- identifiable – cells with known function, easily distinguished
- large – individual neurons up to 1mm
Aplysia exhibit simple learning behaviours relating to repeated/salient stimuli.
- habituation: animal’s reaction to siphon touch (gill retraction) diminishes in intensity with repeated trials
- sensitization: after 13 trials with mild touch stimulus to one body part, the same mild stimulus is delivered at the same time the tail is given an electric shock (this is not strong enough to damage the animal, but it alarms it) – gill retraction response dishabituated (becomes larger again)
Strength of synapses from sensory to motor neurons mirror…
behavioural changes in habituation
METHOD: Possible to use nervous system of Aplysia after removing it from the rest of the animal (a preparation that produces fictive behaviour) to study the changes in the gill withdrawal circuit – electrical stimulation of mechanosensory neuron replaces the actual touch stimulus, and activity of motor neuron represents response size.
- fictive habituation: triggered by repeated electrical stipulation of siphon sensory neuron every 10s (1 AP every ten seconds)
- observation: habituation is mediated by a form of short- to moderate-term synaptic depression at synapse between sensory neuron and gill motor neuron
how it’s expressed – quantal content analysis
Synaptic strength is increased during sensitization, and changes last for tens of minutes.
- fictive sensitization: this stimulation mimics the events that would happen in a behaving animal undergoing sensitization training (siphon nerve stimulation is paired with strong stimuli to the tail nerve)
- observation: single (sensitizing) tail nerve shock induces enhancement of strength of the sensory neuron → motor neuron synapse that can last for tens of minutes after it is triggered
- by the rules for changes in synaptic strength (L13), this plasticity should be called a potentiation – however, Kandel & co. have always referred to it as facilitation, even though it lasts longer than we usually think of facilitation lasting
Long-lasting Sensitization/Facilitation in Aplysia
What is sensitization of sensory motor synapses induced by?
third factor neuromodulator
hypothesis 1: serotonin released onto siphon sensory neuron via axoaxonic synapse is the key stimulus for inducing synaptic plasticity that underlies sensitization
Results of testing the hypothesis that serotonin induces synaptic sensitization.
- exogenous serotonin mimics the synaptic enhancement created by a tail shock stimulus
- controls (not shown here) found that other neurotransmitters are not capable of mimicking tail shock
- depleting serotonin from Aplysia nervous system prevents sensitization from occurring
What is sensitization expressed by?
changes in presynaptic (sensory neuron) axon terminal
- serotonergic interneuron only made axoaxonic synapses
Hypothesis 2: locus of expression will be presynaptic because serotonin acts directly on sensory neuron axon terminal
What is sensitization expressed by?
changes in presynaptic (sensory neuron) axon terminal
- serotonergic interneuron only made axoaxonic synapses
Hypothesis 2: locus of expression will be presynaptic because serotonin acts directly on sensory neuron axon terminal
Results from testing the hypothesis that synaptic sensitization is expressed presynaptically.
- shocking the tail nerve led to broadening of presynaptic AP (this was shown elsewhere to be due to reduction in VG-K currents)
- serotonin mimics effect of tail nerve shock on presynaptic AP
- blocking cAMP breakdown or adding cAMP to the terminal also mimics effect of tail nerve shock on presynaptic AP
Which Gα subunit type is serotonin likely working through?
Gαs (stimulatory) – cAMP is increasing
What is the conclusion of Kandel and co’s experiments on synaptic enhancement in Aplysia?
synaptic enhancement in Aplysia is presynaptic and serotonin-dependent
- induction of sensitization: occurs via activation of facilitatory interneuron
- expression of sensitization: occurs by spike broadening which enhances Ca2+ influx through presynaptic neuron
Short bursts of high frequency stimulation (HFS) cause in stimulated mammalian hippocampal synapses?
shows a form of long-term potentiation that is maintained for hours
After a single tetanus (HFS) to a subset of presynaptic axons, how is the postsynaptic response changed?
postsynaptic response (to single test pulses) is strengthened for at least an hour in axons that received HFS, but control synapses (no presynaptic HFS) are unchanged
Why do most LTP researchers actually report slope of EPSP in its rising phase, NOT amplitude of the peak?
because it’s less affected by noise
LTP (long-lasting enhancement of synaptic strength) triggered by a high frequency tetanus can be observed where?
in all three of the major synapse types in hippocampal trisynaptic circuit
but LTP can have different characteristics depending on the synapse, and be harder or easier to work with, depending on the preparation
