Presentation on theme: "Synaptic Plasticity I: Long-Term Potentiation"— Presentation transcript:
1Synaptic Plasticity I: Long-Term Potentiation 1. The mystery of memory2. The Hebbian synapse & memory3. Long-term potentiation4. Synapse specificity & associativity of LTP5. Phases of LTP6. Pre- versus post-synaptic changes in LTP7. Changes in the shape dendritic spines in LTP8. The connection between LTP & memory9. Can memory be enhanced?
2The Mystery of Memory - Long-term memory is an exotic biological phenomenon…it isencoded immediately, yet canlast for 100 years or more.- Presumably, there are physicalchanges to neurons that underliememory formation…however,the proteins and lipids thatcomprise neurons are turned overevery few hours or days.- How can stable memories be storedby such unstable components?
3Synapses & Memory Capacity - The legendary Spanish neuroanatomistSantiago Ramon y Cajal, who showedthat the brain is not a syncytiumbut is in fact made up of discrete cells,postulated that synaptic connectionsbetween neurons were probablythe sites of memory storage.- There are 10 billion neurons in thehuman brain, with an average of 10,000synaptic connections each…thus, if whole neurons must changeproperties to encode memories, the information storage capacityof the human brain is roughly 10 billion bits, whereas if memoriesare encoded by changes to synapses, then the storage capacityincreases 4 orders of magnitude to 100 trillion bits.
4Hebbian Synapses - In 1949, Canadian psychologist Donald Hebb published “The Organization of Behavior”,an influential book in which he describedhis vision for how synaptic plasticitymight give rise to memory formation.- Hebb’s Postulate: “When an axon of cell Ais near enough to excite cell B or repeatedlyor consistently takes part in firing it,some growth or metabolic change takes place in one or both cellssuch that A’s efficiency, as one of the cells firing B, is increased.”A + B are activeat the same timeweak synapsestrong synapseABABTo put it another way: “Cells that fire together, wire together.”
5Long-Term Potentiation - There are many different forms of synaptic plasticity, whichprobably underlie different types of memory, but the mostintensively-studied example of synaptic plasticity overthe past 40 years has been long-term potentiation (LTP),which can be observed in certain regions of the hippocampusand cerebral cortex.- A lot is now known about LTP,so to help make sense of this massiveamount of information, we will discusswork on LTP chronologically, usingthe history of classic experimentsperformed in this field as an organizingprinciple to understand what ispresently known versus unknown.
6The Discovery of LTP- Terje Lomo & Tim Bliss first described the LTP phenomenonin a 1973 paper that described experiments where theyrecorded from the dentate gyrus (a part of the hippocampus)in anethestized rabbits.- Lomo & Bliss found that when theydelivered a strong tetanic stimulation(for 10 seconds) to the perforant path(the connection between the entorhinalcortex & dentate gyrus), the responsesto test pulses of the perforant pathwere much stronger following thetetanic stimulation…this effect lastedfor at least 3 hours.(from Bliss & Lomo,J. Physiol., 1973)
7Hippocampal Slices - Following the report from Bliss and Lomo, there wereonly a handful of papersabout LTP over the nextfew years, mainly becauseit was very difficult torecord from intact animals.- By the mid-1970’s, therewere great improvementsin understanding how tomake brain slices and keepthem alive for hours in vitro,which allowed work on LTP to proceedon hippocampal slice preparations.
8Synapse Specificity of LTP - Lynch & colleagues demonstratedthat LTP in region CA1 of thehippocampus is specific to onlythe set of synapses receivingthe tetanic stimulation.- This demonstrated thatLTP does in fact represent“synaptic plasticity” ratherthan simply reflectinga change in the globalexcitability of theneurons under study.(based on Dunwiddie & Lynch,J. Physiol., 1978)
9Associativity of LTP - The synapse-specificity of LTP has now been studied in many labs,and it has been widely found thatpairing a weak stimulation of one setof inputs (insufficient on its own tocreate LTP) with a concurrent strongstimulation of another set of inputscan result in LTP of both pathways.- This “associative” property of LTPhas received much attention because it seemsto many neuroscientists to fulfill the prediction ofHebb’s Postulate (“cells that fire together, wire together”).
10Phases of LTP- LTP can be divided into three discrete phases, which have distinctmechanistic underpinnings: induction, expression & stabilization:ExpressionStabilizationInduction(“early LTP”)(“late LTP”)Stable for manyhours, days, weeks
11Induction of LTP Requires Postsynaptic Ca2+ - Lynch & colleagues showedthat injection of calciumchelators such as EGTAinto the postsynaptic neuroncompletely blocked theinduction of LTP.- This finding was soon replicated in many labs and considered verysurprising, since most concurrent work on other types of synapticplasticity (i.e., Kandel’s work on Aplysia, to be discussed in thenext lecture) was focused on presynaptic changes…indeed, somelabs of this era had already claimed to have found increasedglutamate release with LTP, although these findings could notbe consistently replicated in other labs.EGTA(based on Lynch et al.,Nature, 1983)
12Induction of LTP Requires NMDA Receptors - Collingridge & colleaguesshowed that treatment ofhippocampal slices withNMDA receptor antagonists(such as AP5) blocked theinduction of LTP.- It was soon discovered that NMDA receptors are permeable tocalcium and are also voltage-dependent, and thus the mechanismsunderlying LTP induction became quite clear: postsynapticdepolarization facilitated glutamate activation of NMDAreceptors, leading to postsynaptic calcium influx and thegeneration of LTP.AP5(based on Collingridge et al.,J. Physiol., 1983)
13Expression of LTP Requires AMPA Receptors - Lynch & colleaguesshowed that treatment ofhippocampal slices withAMPA receptor antagonists(such as CNQX) masked theexpression of LTP.- Since NMDA-R responses arethe same before & after LTP,this is a further problem for theidea that LTP results fromincreased release of glutamate…recent work has shown anincreased number of AMPAreceptors at potentiated synapses.CNQX(based on Muller, Joly & Lynch,Science, 1988)ControlNMDA receptorsAMPA receptorsPotentiated
14LTP Requires Calcium-Activated Enzymes - Calcium influx through NMDA receptors activates a variety ofdifferent enzymes that are found in the post-synaptic density…the three most intensively-studied enzymes with regard to LTPare the kinases CaMKII & PKC and the protease calpain.- CaMKII and PKC directlyphosphorylate AMPA-R’sto alter their activity andtrafficking, and alsophosphorylate NMDA-R’sand other PSD targets…calpains cleave away atthe cytoskeleton & otherPSD components, resultingin changes to spine shape.NMDACa2+AMPACaMKIIPKCCalpainGlutamateDendriticspine
15The Mystery of Memory - Long-term memory is a very exotic biological phenomenon…it isencoded immediately, yet canlast for 100 years or more.- Presumably, there are physicalchanges to neurons that underliememory formation…however,the proteins and lipids thatcomprise neurons are turned overevery few hours or days.- How can stable memories be storedby such unstable components?
16Changes in Spine Shape Accompany LTP - Stabilization of LTP is accompanied by changes in the shapeand size of dendritic spines…this was first shown by Lynchand colleagues in 1980,and subsequently studiedin exquisite detail byKristen Harris andcolleagues in analysesof 3-dimensional serialreconstructions of spines.- Changes to the shape of dendritic spines can radically alter thecalcium dynamics within the spine, and can also help to makeroom for more AMPA receptors…this can strengthen thesynapse in a stable manner, since the change in shape can bepreserved even as the individual components are turned over.
17Changes in Gene Expression with LTP? - Kandel: “Behavior is the resultof the interaction betweengenes and the environment.”(Ch. 62 of Principles)- Changes in gene expressionhave been found followinghigh-frequency stimulation…however, it is uncertainif these changes play a rolein the stabilization of LTP,as it is unclear how changesin transcription in the nucleuscould give rise to synapse-specific functional changes.CREB“synaptic tagging?”
18LTP & Memory- Does the formation of long-term memories depend on LTP in vivo?…there are several lines of evidence that indicate a connection:1. LTP fits Hebb’s Postulate and is synapse-specific, whichseems a pre-requisite for a biological process that wouldhave a high capacity for information storage.2. LTP is observed in regions of the brain known to be involvedin the formation of long-term memories (hippocampus, cortex)and is either not observed at all, or has very different properties,in other regions of the brain (such as brainstem).3. LTP is induced by brief stimulation and can be very stable,which are properties shared with the formation of long-termmemories.
19LTP & Memory (con’t)4. LTP is optimally induced by brain rhythms associated with learning.- several-second bursts of 100 Hz activitydo not occur naturally, except duringseizures…Larson & Lynch (Science,1986) studied the ability of morephysiological rhythms to induce LTP,and found that separation of briefbursts by 200 msec (a 5 Hz rhythm)is optimal for LTP induction…interestingly, 5 Hz correspondsto the EEG “theta rhythm” observedin the hippocampus and cortexduring learning (and REM sleep).Beta(15-30 Hz)(arousal, alertness, anxiety)Alpha(8-14 Hz)(relaxation, meditation, pre-sleep)Theta(5-6 Hz)(learning, novelty, REM sleep)Delta(1-4 Hz)(deep sleep, unconsciousness)
20LTP & Memory (con’t)5. Drugs or genetic manipulations that block LTP also impair memory.Morris water maze(Morris et al., Nature, 1986)ControlratControl rats rapidlylearn how find thehidden platform.Treatment of rats with theNMDAR antagonist AP5blocks hippocampal LTPand also blocks learningof the platform location.AP5-treatedrat(and later,variousKO mice)
21LTP & Memory (con’t)6. Drugs or genetic manipulations that enhance LTP also enhancecertain types of memory.- Joe Tsien & colleagues (Nature, 1999)created a line of transgenic mice thatover-express the NMDA receptorsubunit NR2B in their forebrains…these mice exhibit enhanced LTPin various hippocampal and corticalregions, and also exhibit significantlyenhanced performance on a number of different memory tasks,including the Morris water maze…thus, the official name forthis line of smart mice is “Doogie”, derived from the brilliantlead character in the TV show “Doogie Howser, M.D.”
22Can Memory Be Enhanced By Drugs? - Cognition-enhancing drugs are commonin our culture…caffeine, for example,blocks inhibitory adenosine signalingin the brain, and hundreds of papers haveshown that caffeine enhances LTP andimproves learning on certain tasks…furthermore, drugs like methylphenidate(Ritalin) and amphetamine (Adderall)enhance the release of dopamine,norepinephrine & serotonin, leading toincreased NMDA & AMPA receptorfunction, enhanced LTP, and improvedperformance of certain memory tasks…problems: cardiovascular side effects,potential for addiction.
23The Future of Memory-Enhancing Drugs - Many companies, including some founded by top LTP researchers,are pursuing the development of memory-enhancing therapeutics:Cortex PharmaceuticalsMemory PharmaceuticalsIrvine, CAFounder:GaryLynchNew YorkFounder:EricKandelConcept: Use AMPA receptor positiveallosteric modulators (“AMPAkines”)to specifically enhance LTP & memory.Currently in Phase II clinical trials.Concept: Use phosphodiesterase inhibitorsto slow the breakdown of cAMP, enhanceCREB activation, and improve memory.Currently in Phase II clinical trials.PDE inhibitorsPDEPKAcAMPAMPAkines