Lecture 7 - Synaptic Plasticity & Learning PDF

1 LECTURE 8: SYNAPTIC PLASTICITY & LEARNING PROF. JUNIOR STEININGER 2 THERE ARE MANY DIFFERENT FORMS OF SYNAPTIC PLASTICITY IN RESPONSE TO REPETITIVE ACTIVITY Synaptic Plasticity: activity-dependent changes in synaptic strength 1. Short-term synaptic pl...

1 LECTURE 8: SYNAPTIC PLASTICITY & LEARNING PROF. JUNIOR STEININGER 2 THERE ARE MANY DIFFERENT FORMS OF SYNAPTIC PLASTICITY IN RESPONSE TO REPETITIVE ACTIVITY Synaptic Plasticity: activity-dependent changes in synaptic strength 1. Short-term synaptic plasticity (a few minutes or less) Strengthening or weakening of synaptic transmission Many different types, varying in time course and mechanism Most forms affects amount of transmitter released 2. Long-term synaptic plasticity (30 mins or longer) Long-lasting strengthening or weakening of synaptic strength in mammalian brain (e.g., LTP, LTD) Changes in circuit function leading to behavioral plasticity, and may serve as cellular correlate of learning and memory 3 ONGOING ACTIVITY CAN RESULT IN SHORT-TERM CHANGES IN THE SYNAPTIC EFFICACY VIA CHANGES IN TRANSMITTER RELEASE 4 POST-TETANIC POTENTIATION (PTP) IS ELICITED BY LONGER AND HIGH- FREQUENCY TRAINS OF STIMULI This “tetanus” stimulation elicits synaptic depression, followed a few seconds later by an increase in PSP amplitude Lasts for tens of minutes  ACTIVITY-DEPENDENT CHANGES IN SYNAPTIC 5 EFFICACY CAN ALSO OCCUR ON MUCH LONGER TIMESCALES (HOURS!) Long-Term Potentiation (LTP): activity-dependent, longlasting increase in synaptic strength Long-Term Depression (LTD): activity-dependent, longlasting decrease in synaptic strength LTP/LTD are broad terms – many different mechanisms can be involved 6 DEFINED, UNIDIRECTIONAL ROUTES FOR INFORMATION FLOW ALLOW TARGETED STIMULATION TO STUDY SYNAPTIC FUNCTION 7 BLISS & LOMO (1973) FIRST DEMONSTRATED THAT TETANUS STIMULATION PRODUCED POTENTIATED RESPONSE LASTING HOURS Stimulating perforant path, recording dentate granule cells Each tetanus created an increase in EPSP amplitude  8 IMPORTANT PROPERTIES OF LTP 1. Experience-dependent: needs stimulation to induce a large change in synaptic strength 2. Induced rapidly: stimulation applied for only a few seconds can lasts hours 3. Cooperativity: there is a stimulus intensity threshold for the induction of LTP 4. Coincident activity: coordinated activation between presynaptic and postsynaptic cells 5. Input-specificity: only activated pathways are potentiated 6. Associativity: Co-activation of separate but converging input can induce LTP; must be in close temporal order 9 EXPERIMENTAL EVIDENCE FOR 3 IMPORTANT PROPERTIES OF LTP S2 stimulation alone is insufficient to induce LTP, falling below the cooperativity stimulus intensity threshold 10 EXPERIMENTAL EVIDENCE FOR 3 IMPORTANT PROPERTIES OF LTP S1 stimulation is sufficient to induce LTP, but demonstrates input specificity by not inducing LTP at S2 pathway as well 11 EXPERIMENTAL EVIDENCE FOR 3 IMPORTANT PROPERTIES OF LTP Simultaneous tetanus to both inputs allowed for the weak S2 input to benefit from being associated with strong S1 input 12 COINCIDENT ACTIVITY EMPHASIZES IMPORTANCE OF PAIRING PRESYNAPTIC AND POSTSYNAPTIC ACTIVITY Single pulse to SC axons do not induce LTP on their own. But, LTP is induced if stimulus paired with depolarization of CA1 via recording electrode 13 LTP AS THE CELLULAR ANALOG OF ASSOCIATIVE LEARNING 14 LTP AS THE CELLULAR ANALOG OF ASSOCIATIVE LEARNING 15 LTP AS THE CELLULAR ANALOG OF ASSOCIATIVE LEARNING 16 HOW LONG CAN LTP LAST? Longest in vivo experiment has tested up to 1 year later! Length usually depends on number of stimulation trains given 17 LONG TERM DEPRESSION (LTD) CAN BE TRIGGERED BY REPETITIVE LOW FREQUENCY STIMULATION TO REDUCE THE SIZE OF THE EPSP 18 IMPORTANT FEATURES OF LTD Like LTP, it can last for several hours and shows input specificity to the activated synapse LTD can be considered the opposite of LTP -> it is a way of reducing the connection between two brain regions or cells LTD can erase the increase in EPSP size due to LTP (and vice versa) Complementarity: LTD and LTP reversibly affect synaptic efficiency by acting at a common site  19 HOW CAN WE ACCOUNT FOR THE FEATURES OF LTP? 20 WE WANT TO UNDERSTAND THE UNDERLYING MECHANISMS INVOLVED WITH LTP TO EXPLAIN ITS PROPERTIES E.g. ‘cooperativity’: At the cellular level, why is it that strong but not weak stimulation induces LTP? 21 LTP OFTEN DEPENDS ON ACTIVATION OF NMDA RECEPTORS Drugs that block the NMDARs (e.g., AP5) prevents LTP induction in most cells, without affecting baseline responses RECALL: What are the special features of NMDA receptors? How could that explain this? High relative permeability to Ca2+ (But NA+ and K+ too) Voltage gated At Rm pore if blocked by Mg2+ 22 THE NMDA RECEPTOR BEHAVES AS A COINCIDENCE DETECTOR The channel opens (to induce LTP) only when these two events occur simultaneously: (1) glutamate is bound to the receptor (2) postsynaptic cell is depolarized (via AMPARs) to relieve Mg2+ block 23 DIFFERENT MECHANISMS UNDERLIE THE INDUCTION, EXPRESSION AND MAINTENANCE PHASES OF LTP 1. Short-Term Potentiation (STP): minutes to 1 hour (induction) NMDAR and postsynaptic Ca2+-dependent 2. Early-LTP (E-LTP): 1-5 hours (expression) Protein kinase dependent (but protein synthesis independent) 3. Late-LTP (L-LTP): many hours to years (maintenance) Protein synthesis and RNA transcription dependent 24 INCREASED CA2+ IN THE POSTSYNAPTIC CELL IS THE TRIGGER FOR LTP INDUCTION [Ca2+] in serves as a 2nd messenger signal that induces LTP Induces LTP by activating signal transduction cascades via CaMKII and PKC Injection of Ca2+ chelators blocks LTP induction Accounts for first ~1 hr 25 HOW IS LTP ACTUALLY EXPRESSED? Strengthening of synaptic transmission during LTP arises from an increase in the sensitivity of postsynaptic cell to glutamate This could occur through at least 6 mechanisms, expressed on the presynaptic or postsynaptic side 26 HOW IS LTP ACTUALLY EXPRESSED? Strengthening of synaptic transmission during LTP arises from an increase in the sensitivity of postsynaptic cell to glutamate This could occur through at least 6 mechanisms, expressed on the presynaptic or postsynaptic side 27 ACTIVATION OF SILENT SYNAPSES IS ONE OF THE MAJOR FACTORS CONTRIBUTING TO POSTSYNAPTIC EXPRESSION OF EARLY-LTP 28 LATE-LTP DEPENDS ON CHANGES ON GENE EXPRESSION AND THE SYNTHESIS OF NEW PROTEINS TO MAINTAIN THE POTENTIATION 29 LONG-LASTING (POSSIBLY PERMANENT?) LTP CHANGES INVOLVE INCREASES TO THE NUMBER AND SIZE OF SYNAPTIC CONTACTS New dendritic spines can be observed as early as ~1hr after a stimulus that induces LTP The shortening/widening of spine necks has also been reported, which would reduce its electrical resistance and increase synaptic efficacy 30 LTD MECHANISMS ARE SIMILAR TO THOSE FOR LTP LTD also requires activation of NMDA receptors and the resulting entry of Ca2+ for induction Small and slow rises in Ca2+ = LTD Large and fast increases in Ca2+ = LTP Activation of Ca2+-dependant phosphatases Loss (internalization) of AMPA receptors 31 SUMMARY OF IMPORTANT CONCEPTS Short periods of synaptic activation can result in facilitation, depression, or augmentation of transmitter release, or a combination of these effects Facilitation decays gradually over a few hundred milliseconds, while synaptic depression and augmentation persist for several seconds Facilitation is related to a persistent increase in cytoplasmic calcium concentration in the presynaptic terminal Longer periods of repetitive stimulation result in PTP of transmitter release, which can last for tens of minutes and is mediated by an increase in presynaptic terminal calcium concentration 32 SUMMARY OF IMPORTANT CONCEPTS In various parts of the CNS, repetitive stimulation can result in activity-driven LTP or LTD of synaptic strength The change in synaptic efficacy during LTP or LTD may be homosynaptic, involving only the stimulated input, or heterosynaptic, affecting adjacent synapses on the same dendrite Heterosynaptic effects may be associative, requiring the coordinated activation of both synapses LTP is produced by an increase in calcium concentration in the postsyanptic cell and involves both the insertion of new receptors into the postsynaptic membrane and an increase in receptor sensitivity 33 SUMMARY OF IMPORTANT CONCEPTS LTD also requires an increase in postsynaptic calcium concentration and is mediated by a decrease in receptor number and sensitivity Both LTP and LTD can also involve changes in transmitter release from the presynaptic terminal Although there are some correlations between LTP and LTD and behavioural tasks involved in learning, no unequivocal relation between these long-term synaptic changes and memory formation have been established  34 LTP AS A MECHANISM UNDERLYING MEMORY 35 IS LTP THE MECHANISM UNDERLYING LEARNING AND MEMORY? Four criteria must be fulfilled: DETECTABILITY: Memorable events should induce detectable changes in synaptic efficacy (LTP) ANTEROGRADE ALTERATION: Preventing LTP before/during a learning experience should impair memory of that experience RETROGRADE ALTERATION: Altering the synaptic weight changes induced by a prior learning experience should alter the memory of that experience MIMICRY: Artificial induction of synaptic weight changes could induce a memory for some past experience which did not actually occur  36 #1. DOES LEARNING INDUCE LTP? 37 LEARNING-INDUCED LTP Two-chambered box (light- dark box): a lighted safe side and a dark shock side, separated by a trap door Inhibitory Avoidance Paradigm: rats learn to avoid the chamber side associated with shock (as measured by longer latency to enter). Control groups? 38 LEARNING-INDUCED LTP Whitlock et al., (2006) trained rats in an inhibitory avoidance paradigm. Training consisted of allowing rats to cross from an illuminated chamber into a dark chamber where a foot shock was delivered. Memory of this experience was measured as the tendency for the animals to avoid the dark side in subsequent trials (expressed as the time(latency) it took animals to enter the dark chamber from the light side). Inhibitory avoidance training resulted in an enhancement in Ser831 phosphorylation, and an increase in GluR1 and GluR2 protein levels, indicating LTP induction. 39 LEARNING-INDUCED LTP Two-chambered box (light-dark box): a lighted safe side and a dark shock side, separated by a trap door Inhibitory Avoidance Paradigm: rats learn to avoid the chamber side associated with shock (as measured by longer latency to enter). Control groups: walk-through (with no shock), Shock-only, naïve 40 LEARNING-INDUCED LTP Additional cellular markers indicated LTP occurred after inhibitory avoidance: increases in GluR1 & GluR2 protein expression and phosphorylation of receptors Cellular markers for LTP exist (serving as an important control), but can they directly demonstrate that a learning experience caused potentiation of synaptic activity? 41 INHIBITORY AVOIDANCE LEARNING INDUCED LTP Inhibitory avoidance training results in enhancement of fEPSPs in CA1 Fairly weak change, but does provide the necessary in vivo demonstration Obscured in group fEPSP average (A) because only a subpopulation of electrodes are detecting the effect (E) 42 #2. PREVENTING LTP BEFORE/DURING A LEARNING EXPERIENCE SHOULD IMPAIR MEMORY OF THAT EXPERIENCE 43 WATER MAZE: TESTING SPATIAL REFERENCE MEMORY Training: Rats learn to find an escape platform in a fixed location using extra-maze (spatial) cues. HPC-lesioned rats show increased latency of finding platform. 44 WATER MAZE: TESTING SPATIAL REFERENCE MEMORY Training: Rats learn to find an escape platform in a fixed location using extra-maze (spatial) cues. HPC-lesioned rats show increased latency of finding platform. 45 WATER MAZE: TESTING SPATIAL REFERENCE MEMORY Transfer Test: Rats are assessed on where (which quadrant) they spend the most time swimming in, when the platform is not present. Experimenters measure which quadrant the rat would spend most time in. 46 PREVENTING LTP 47 WATER MAZE PERFORMANCE WITH AP5 INTRA-VENTRICLE ADMINISTRATION OF AP5 (NMDAR ANTAGONIST) BLOCKS LTP INDUCTION IN HIPPOCAMPUS 48 WATER MAZE PERFORMANCE WITH AP5 AP5 INCREASES LATENCY (I.E. TIME) TO FIND PLATFORM DURING TRAINING 49 WATER MAZE PERFORMANCE WITH AP5 AP5 IMPAIRS MEMORY OF PLATFORM LOCATION DURING TRANSFER TEST 50 PREVENTING LTP 51 WATER MAZE PERFORMANCE IN CAMKII MUTANTS 52 WATER MAZE PERFORMANCE IN CAMKII MUTANTS...but CaMKII mice are also impaired at swimming to a visible platform (not something seen with hippocampal lesions)  53 PREVENTING LTP 54 GENETIC MANIPULATION OF AMPARS GLUA1 = GLUR-A = GLUR1  DIFFERENT NAMES FOR SAME SUBUNIT 55 IN KO MICE LACKING GLUA1 SUBUNIT LTP is impaired at CA3 -> CA1 synapse But, no water maze deficits! 56 T-MAZE (REWARDED ALTERNATION): TESTING SPATIAL WORKING MEMORY 57 T-MAZE ALTERNATION PERFORMANCE WITH GLUA1 KO MICE Whereas GluA1 KOs had no problems with their water-maze performance, they are impaired in the T- maze alternation task 58 PREVENTING LTP 59 CA1-SPECIFIC GENETIC KO OF NR1 SUBUNIT 60 SPATIAL REFERENCE MEMORY IN CA1-NR1 KOS WATER-MAZE PERFORMANCE (I.E. SPATIAL REFERENCE MEMORY) IS IMPAIRED IN CA1-NR1 KO MICE 61 DENTATE GYRUS SPECIFIC NR1 KNOCKOUT IMPAIRED LTP INDUCTION FOLLOWING PERFORANT PATH STIMULATION 62 SPATIAL REFERENCE MEMORY IN DG-NR1 KOS 63 SPATIAL WORKING MEMORY IN DG-NR1 KOS 64 HIPPOCAMPAL LTP = SPATIAL MEMORY? Hippocampal LTP: reliable experimental model of synaptic plasticity If hippocampal LTP underlies spatial learning and memory then inhibiting LTP before/during spatial learning should impair memory AP5 inhibits LTP: Impairs spatial learning and memory in watermaze Genetic knock-out of GluA1 (AMPA) or NR1 (NMDA) subunit inhibits LTP But no spatial reference memory impairments GluA1 /NR1-dependent LTP is not necessary for spatial reference memory BUT GluA1/NR1-dependent LTP is necessary for spatial working memory 65 IS LTP REALLY A MEMORY MECHANISM? View that LTP = memory mechanism continues to be popular, but perhaps it’s because there’s no better candidate/theory to replace LTP! Does LTP last long enough to act as a memory device? Memories can persist intact throughout the life span of the animal, whereas LTP eventually decays. But locus of memory may transfer after LTP induction, and there’s also evidence of long lasting changes in dendritic morphology. Animals have demonstrated intact learning ability in the absence of LTP. Some pharmacological and genetic manipulations that eliminate the capacity for LTP induction produce no deficit in learning (e.g., water maze, radial maze testing long term memory acquisition). Rats will still eventually learn even when NMDARs are blocked During development, memories can be formed because NDMARs are expressed Perhaps different forms of synaptic plasticity underlie different forms of learning/memory, and interpretation of these effects is confounded by the variability in brain structures necessary for successful completion of the task, the potential effects of the manipulations on sensory and motor performance, and the neuroanatomical deformities induced by the genetic manipulation.