HMB200H1 Final: L6 How can Synapses Change?

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Human Biology
Franco Taverna

Lecture 6 How can Synapses Change? Kolb & Whishaw 5E: §14.1, 14.4, 5.4 Sumanasinc “Sensitization” and “AMPA and NMDA” Long-term Potentiation Short Video Module, Timing of Synaptic Plasticity Video Tuesday, February 28 Lecture Outline: I. Hebb’s Postulate II. Changes in Synaptic Signaling • Changing the function of the synapse III. Evidence for Hebbian Plasticity IV. Mechanisms of Synaptic Changes a. Habituation b. Sensitization c. Hebbian Plasticity Key Principle of Neuroscience Nervous system functions are constantly changing, an attribute called • Neuroplasticity occurs at the synapse, itself neuroplasticity. • APL says that the brain is, by design, molded by • “The brain, as the source of human behaviour, is by design molded by environmental changes – experience alters brain organization, via the mechanism of neuroplasticity, and is environmental changes and pressures, physiological modifications, and required for survival, learning, and memory experiences.” APL • Plasticity should be measurable at the structural level but • Experience alters the brain’s organization also at the synapse • Neuroplasticity is required for development, learning, and memory functions, as well as for survival • New information can be stored in nervous system if and only if neural connections change Plasticity, therefore, should be measurable, as changes in brain structure and/or synaptic connections. The Brain as a Moving Target “…plasticity is not an occasional state of the nervous system; instead, it is the normal ongoing state of the nervous system throughout the life span.” APL • If default function of the brain is to change, it’s difficult to study because what do we call baseline • In order to measure behaviour appropriately, we have to • “The brain is like a moving target” measure things relative to a prior state (before and after • Therefore, to measure plasticity, you must measure relative to a prior intervention), as close to static state state (before the manipulation Donald O. Hebb • Worked with Wilder Penfield at Montreal Neurological • Hebb’s Law: cells that fire together, wire together Institute • The connection between A and B is increased in efficiency – the o Concluded that memory is distributed, rather than synapses between them strengthen localized, based on brain surgery studies • This was a proposal by Hebb, and it wasn’t until decades later when evidence started accumulating for this The Organization of Behaviour 1949, McGill University • “When axon of cell A is near enough to excite cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficacy, as one of the cells firing B, is increased.” • “Neurons that fire together, wire together” (i.e., the synapses between them strengthen) Synaptic Signaling can be Remarkably Consistent, Given the Same Stimulus For a given stimulus (e.g., injecting positive charges into axon), BUT, Hebb’s postulate suggests that synaptic signaling can change… • Same frequency of action potentials (Rate Law) how and why? • Same amount of neurotransmitter released • Deflections often change depending on how it’s published • Same response (i.e., amplitude of PSPs) • If you simply stimulate axon of presynaptic neuron, the postsynaptic neuron will respond in a relatively similar way each time you stimulate it (all or none response) – so there is some consistence But…the system can change. And it can also change = plasticity • They sum here, but given same initial stimulus, we get a different post synaptic response based on something • It can stay the same or it can change Synaptic Signaling can also Change in Either Direction Change = Plasticity For the same initial stimulus as before (e.g., injecting positive charges into axon), • Same frequency of action potentials (Rate Law) • Different amount of neurotransmitter released • Different level of response (i.e., amplitude of PSPs) E.g., reflex circuit – presynaptic (sensory) neuron & postsynaptic (motor) neuron • First Discovery of Synaptic Plasticity in Mammals: Rabbit Hippocampi • Used brain tissue from rabbits and sliced hippocampus o Hippocampus important for learning and memory, and of all brain regions, it’s one of the simplest structurally 2 Measuring Synaptic Signaling in the Hippocampus Cross-section of mammalian hippocampus: • Hippocampus seems to be evolutionarily older, with III layers of cells, rather than 6 like the cortex • All the circles represent cell bodies • AD = dentate gyrus, with horseshoe shaped area of cell bodies • Send axons to CA3 region of the hippocampus o Black line are axons that connect to thousands of CA3 dendrites • CA3 neurons send axons that connect to dendrites of CA1 neurons • Perforant path: bundle of axons from entorhinal cortex that synapse onto dendrites of dentate gyrus neurons • PP is the performant path, represents bundle of axons from the entorhinal cortex (adjacent to hippocampus), which synapse onto cell bodies of dentate gyrus neurons Structurally, we can place two electrodes, one in dendritic field in dentate gyrus, and one in the performant path axons. • Axons will fire population spikes and we can record the postsynaptic response • Plot amplitude of EPSP and then plot means of amplitude o Same level of response normalized to 100% Stimulate and Record 1. Stimulate: population spikes in PP axons • All the dots represent stable level of EPSP that happens with same 2. Record: population EPSPs in DG dendrites level of stimulation 3. Record: population spikes in DG neurons • We can also record in the cell body/axon level of those same neurons – population spike for same collection of neurons Note: Population spikes are action potentials 3 Long-Term Potentiation Bliss and Lomo original figure: • Fired high-frequency burst of stimuli to axons in PP, and then returned to original strength of stimulus • For the same original stimulation, they noticed that the response was much larger • Amplitude of EPSP is much greater, and it’s approx. 200- 300% more • It starts off very high after high-frequency stimulation, then gradually decreases to an amplitude to still rests above the original baseline • This is truly an increased response to the same level of stimulation because the synapse is more sensitive (i.e., enhanced) • Each dot represents the amplitude of the EPSP in response to one weak test stimulation • HFS given at arrows o EPSP increases after each one o Long-term potentiation of the EPSP • Baseline response (non-HFS pathway) shows steady consistent EPSPs for a given stimulus Strong High-Frequency Stimulation Can Change Subsequent Responses Bliss and Lomo called this long-term potentiation (LTP). • Individual dots are EPSP responses to stimuli, and we see averages before and after HFS • This was first evidence in mammalian system that showed that Hebb’s postulate might actually be correct Note: each dot represents the amplitude of the EPSP in response to one weak test stimulation. Summary: LTP Illustrated with One Synapse • HFS is strong enough to fire action potential in postsynaptic neuron • After HFS, response is enhanced 4 “Neurons that fire together, wire together” • Cell A was stimulating cell B, and the connection between them Donald O. Hebb (The Organization of Behaviour, 1949) was enhanced • “When axon of cell A is near enough to excite cell B and • We represent these as two signal neurons, but the reality of repeatedly or persistently takes part in firing it, some growth experimentation, we are looking at thousands of axons and process or metabolic change takes place in one or both cells dendrites such that A’s efficacy, as one of the cells firing B, is increased” • HFS accomplishes this o Presynaptic neurons are stimulated strong enough to fire postsynaptic neurons • Strong enough EPSP to trigger an AP Plasticity Goes Both Ways • There are ways of stimulating that you can get the opposite of • Neurons that fire together, wire together enhancement (synaptic depression) – the synapse gets weaker for • Neurons that fire apart, wire apart the same stimulus • This occurs in refinement of ocular dominance columns (peripheral connections weaken, shrink, and disappear) • With HFS, we get enhancement E.g., Spike timing (history) dependent plasticity o HFS is artificial and doesn’t happen in the brain (one • Neurons show different responses (and changes) as a function of criticism for decades), but timing stimulation occurs in prior input vitro as well, triggering the same kinds of mechanisms • Repeated presynaptic spike arrival < 20ms before postsynaptic • With LFS, we can get depression • Timing of the two neurons also comes into play action potentials leads to LTP • Repeated presynaptic spike arrival < 20ms after postsynaptic o If A fires an AP just before B fires an AP, these conditions lead to synaptic enhancement action potentials leads to LTD o This happens if A is the one that’s firing B o If A fires an AP just after B fires an AP, these conditions lead to synaptic depression timing_dependent_plasticity ▪ Occurs when B has other inputs (stronger) Why might timing be an important determinant of plasticity and/or direction of plasticity (potentiation or depression)? • A  B could represent causality, and associations • B  A could represent non-causal associations 5 Summary: Synaptic Plasticity • Certain kinds of presynaptic stimulation can lead to potentiation of the post-synaptic response o Cells that fire together, wire together o Presynaptic firing < 20ms before postsynaptic activation o Stimulation that is strong enough to cause action potentials in the postsynaptic neuron (i.e., HFS ~ 100Hz) • Other kinds of presynaptic stimulation can lead to depression of the postsynaptic response o Cells that fire apart, wire apart o Presynaptic firing > 20ms after postsynaptic activation o Low frequency stimulation (i.e., ~ 1Hz) Mechanisms of Synaptic Plasticity Eric Kandel, Nobel Prize Winner • Can use reflex circuits (sensory to motor behavioural circuits) to record and stimulate • Studied learning and synaptic changes in giant sea slug, • Aplysia can learn – mechanisms of short and long term memories Aplysia californica are conserved throughout invertebrate and vertebrate world, • Simple system (1000 neurons in ganglion) including humans o Neurons can be recognized and recorded from, and connections traced From Learning Behaviour to Synaptic Mechanisms • Pinsker H, Kupfermann I, Castellucci V, and Kandel E. (1970) Habituation and dishabituation of the GM-withdrawal reflex in Aplysia. Science 167:3926(1740-1742). Doi: 10.1126/science.167.3926.1740 • In Search of Memory by Eric R. Kandel 6 Aplysia Gill Withdrawal Reflex (GWR) This is an easy model to study learning mechanisms. • Gill withdrawal reflex (GWR): touch the siphon, gill is withdrawn into shell for protection • A gentle touch to the gill will cause gill withdrawal (monosynaptic GWR) • This will also occur with gentle touch to the mantle Habituation of GWR Habituation: learning behaviour in which a response to a stimulus • With repeated innocuous stimulation, the GWR gets weaker weakens with repeated stimulus presentations and weaker, and eventually it doesn’t withdraw it’s gill at all • This is a natural response called habituation o Tidal pools with repeated wave action in natural environment o Habituation conserves energy • Simple form of nonassociative learning The withdrawal response weakens with repeated presentation of water jet (habituation) owing to decreased Ca influx and subsequently less neurotransmitter release from the presynaptic axon terminal. What are some examples of habituation? Habituation and Dishabituation • Habituation of responses to repeated light stimuli • Habituation is easily reversed o E.g., another stimulus, delay (of approx. 90 minutes), etc. o Dishabituation • Implies very rapid changing of stimulus  response • GWR habituates and then if you stop the stimulation and return to it later, the GWR gets restored 7 Mechanism of Habituation of GWR Short term presynaptic plasticity  dishabituation occurs easily 2+ With habituation, the influx of Ca in response to an action potential decreases resulting in less neurotransmitter released at the presynaptic membrane and less depolarization of the postsynaptic membrane. Mechanism of reduced EPSP in this case: • Ca channels are modified and allow to less Ca to enter, resulting in less neurotransmitter being released with each action potential • Sensory and motor neuron still fired APs at the same level, so there wasn’t anything happen with respect to APs • The synapse between the two was very rapidly changing, decreasing in efficacy • The mechanism – calcium channels at end of axon of sensory neuron changed function to have less calcium influx when action potential arrives, leading to less release of neurotransmitters, and less response on postsynaptic membrane • Dishabituation – reversing of calcium channel behaviour to original Answer: Why does short term habituation of GWR occur? A. Less neurotransmitter is released for a given stimulus. Answer: Which statement is correct about snail GWR? C. • This is short term learning (habituation and dishabituation) Check Your Understanding 1. Why does short-term habituation of GWR occur? a. Less neurotransmitter is released for a given stimulus b. Snails need to escape predators c. The synapse shrinks in size d. Action potentials in the sensory neuron are smaller 2. Why does the GWR return to normal after a delay? a. Neurotransmitter levels return to normal b. Short-term plasticity is permanent c. Every morning, the snail needs to escape predators d. Invertebrates are not capable of long-term changes to neural systems 3. Which statement is correct about snail GWR? a. Dishabituation is caused by growing synapses b. Dishabituation happens because invertebrates are not capable of long-term changes to neural systems c. Dishabituation occurs because neurotransmitter levels return to previous higher levels d. Dishabituation is caused by larger action potentials in the sensory neuron 8 Long-Term Habituation of GWR • If you repeatedly habituate the animal, it tends to return • Repeated blocks of habituating stimuli result in long-term habituation of GWR towards normal • After a few days, the baseline level of the next day gets smaller and smaller • Slope (speed of habituation) increases – animals habituate quicker and quicker • Afterwards, we have a permanent decrease of GWR Mechanisms of Long-Term Habituation of GWR • Applying actinomycin D (RNA transcription inhibitor) reduces • Following same protocol in presence of inhibitor blocks long- long-term habituation term habituation, even though short term habituation occurs • Longer term potential requires protein transcription • We can get rapid changes at the synapse (altering channels, etc.), but for longer term and more permanent changes, we need protein transcription and translation which can lead to structural changes o Genes could relate to polymerization/depolymerization of actin, or kinases, leading to more permanent changes Esdin J, Pearce K, and Glanzman DL. (2010) Long-term habituation of the gill-withdrawal reflex in Aplysia via transcription, calcineurin and L-type voltage-gated calcium channels. Front Behav Neurosci 4:181 Long-Term Habituation of GWR Mechanisms: • Synapse number/size is reduced (proteins/enzymes to remodel axon/synapses) • E.g., actin depolymerization (unknown postsynaptic mechanisms) Check Your Understanding 4. Which statement is correct about long-term habituation of Aplysia GWR? a. Long-term habituation occurs because snails need to escape predators b. Less neurotransmitter is released for a given stimulus c. Action potentials in the sensory neuron are smaller d. The muscle is weakened 9 Short- and Long-Term Plasticity • Short and long-term habituation is an example of typical • Molecular changes, protein receptor changes, are short term dynamics of neural plasticity (short  long-term changes) changes • Long term changes are more structural in nature Donald Hebb, a Canadian scientist, first hypothesized about • Learning activates change in neural circuit – with sufficient activity, neural plasticity: long term changes can take place Dual trace hypothesis: • Long-term stable learning takes more effort and time to make the • Learning activates a change in a neural circuit (short-term) changes permanent • Sufficient activity builds up more stable changes (long- lasting memory trace) “One should not pursue goals that are easily achieved. One must develop an instinct for what one can just barely achieve through one’s greatest efforts.” – Albert Einstein Sensitization of Aplysia GWR, An Example of Synaptic Facilitation Sensitization: learning behaviour in which the response to a stimulus strengthens with repeated presentations of that stimulus because the stimulus is novel or stronger than normal (homosynaptic) • Sensitization of a weak stimulus can also occur if it’s paired with a strong stimulus (heterosynaptic) • Sensitization is a form of potentiation • Habituation and sensitization are nonassociative, so they’re very simple forms of learning that occur in the same circuit • With gentle touches to the siphon, a moderately intense (noxious) stimulus to the tail, and going back to the same stable LFS of the siphon, the GWR enhances • Simple model for PTSD, response is much larger to a mild stimulus Mechanisms of Sensitization of GWR Very strong stimuli will cause sensitization of the weak stimuli. Heterosynaptic sensitization (weak stimulus paired with strong stimulus) • An interneuron receives input from a shocked sensory neuron in the tail and releases serotonin onto the axon of a siphon sensory neuron • It’s part structural and part molecular within the synapse • Strong stimuli to the tail gets felt throughout the synapses, including the sensory – motor synapse of GWR 10 Mechanisms of Sensitization (Short-Term Changes) + Presynaptic mechanism: serotonin  receptors  protein kinase A (PKA)  activate protein kinase C (PKC)  phosphorylate K channels (reduce function)  less hyperpolarization  phosphorylate Ca channels (enhance function)  increased Ca influx  2+ increased neurotransmitter release  greater postsynaptic response Postsynaptic mechanism: serotonin  receptors  increase membrane receptor recycling  more receptors expressed on membrane  greater postsynaptic response • Through sophisticated and molecular work, synapse is strengthened because of signaling pathways are changes • K channels on presynaptic neuron (that repolarize the cell after AP) are phosphorylated (post-translational modification – kinase is activated by strong stimulation) – lowering their functioning, making less permeable to K, so less hyperpolarization (so presynaptic becomes more depolarized for given AP) • Calcium channel is enhanced via phosphorylation by kinase resulting in more Ca influx for given AP • All results in more NT release per AP, and more postsynaptic response • More receptors expressed on post synaptic side contributes to increase efficacy of synapse • From one AP to the next, phosphorylation can enhance the function of the synapse Repeated Sensitization Can Lead to Long-Term Changes via Synapse Growth Mechanism: repeated shocks  strong signaling from interneuron  serotonin  G-protein induced signaling to nucleus  genes transcribed  synaptic growth • Longer term changes can take place if stimuli are repeated or strong, leading to synaptic growth – the whole circuit expands 11 Summary: Short and Long-Term Sensitization Mechanisms • 5-HT is the neurotransmitter that activates receptors to activate AC that creates cAMP which binds to and activates PKA – phosphorylates K channel – and PKC – phosphorylates Ca channel • Phosphorylate other proteins that signal back to the nucleus transcription factors that activate gene transcription and lead to expression of genes that lead to synaptic growth • This all takes time, so growth piece and permanent larger changes in synapses are typically longer-term o May not happen right away, will need repeated stimuli to get longer term growth to occur Check Your Understanding 5. What happens if you phosphorylate presynaptic K channels? a. Less neurotransmitter release b. More inhibition c. Less hyperpolarization d. More repolarization 6. What happens if you insert more serotonin receptors in the postsynaptic membrane? a. Less neurotransmitter release b. Less excitation c. More hyperpolarization d. More depolarization 12 Summary: Habituation and Sensitization • We’re going from behaviour, parsing apart • Habituation: a progressive decrease in response to a repeatedly presented stimulus changes in molecular and structural o Short- and long-terms functions, and looking at the resulting o Nonassociative learning: change of the behaviour of an animal due to an behaviour experience from specific kinds of stimuli o Single pathway stimulated is changed (no associations made) • Sensitization: an increase of a response due to the pr
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