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Lecture 7

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Rutsuko Ito

Lecture 7 Synaptic plasticity and learning Lecture outline Synaptic plasticity: 1. Donald Hebb (1949): a. Hebb's Law: Neurons that fire together wire together i. "When an 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 efficiency, as one of the cells firing B, is increased" 2. Classical conditioning explained by Hebbian learning 1. Pavlov and the dog Synaptic plasticity 1. Increase in synaptic strength: a. Long Term Potentiation (LTP) i. Enhancement of field EPSP as you deliver a high frequency ... 2. Decrease in synaptic strength: a. Long Term Depression (LTD) 3. Stratum radiatum  dendrites a. Field potential recordings occur here 4. Stratum pyramidale  cell bodies Long term potentiation 1. Bliss and Lomo 1973 a. Anaesthetised rabbit i. Insert stimulating electrode into perforant path axons ii. Insert recording electrode into dentate gyrus iii. Give test pulses at 0.5 Hz 1. i.e. one pulse every 2 s 2. Baseline field potential iv. Stimulate PP ('tetanus') 1. e.g. a. 15 Hz for 15 s i. or b. 100 Hz for 3 s v. Give test pulses at 0.5 Hz 1. Is the new field potential the same as baseline? b. Results i. Slide 8 LTP in awake, freely moving rabbits 1. Bliss and Gardner-Medwin 1973 a. LTP: i. Lasting 3 days (single trains) ii. Lasting weeks (multiple trains) Important properties of LTP (CIA) 1. Cooperativity a. When using high frequency stimulation to induce LTP, a crucial number of presynaptic fibers must be simultaneously activated i. i.e. they must cooperate to elicit LTP (a threshold stimulation strength must be used) 2. Input specificity a. Once induced, LTP at a single synapse does not spread to another 3. Associativity a. Co-activation of separate but converging input can induce LTP when stimulation of either of these pathways alone is incapable of inducing LTP i. E.g. a weak input can sustain LTP if concurrently paired with a strong input 1. Association must be in close temporal order LTP across single synapses 1. Pairs of synaptically connected CA3  CA1 neurons (in vitro slices) a. LTP induction: i. 40 pairings of pre and post synaptic activity 1. = increase in EPSC amplitude Long term depression 1. Repetitive low frequency stimulation of Schaeffer collaterals reduces field potential size What is the role of synaptic depression? 1. Simplistic view: a. Enhancing signal-noise ratio b. Forgetting mechanism (reversal of LTP) c. Erasing stored information 2. Complex view: a. Evidence that LTD is a 'learning' mechanism encoding aspects of novelty acquisition b. LTD is facilitated during novel object exploration and novel object in place exploration i. Inhibition of LTD when exploring empty holeboard ii. LTP is facilitated by exploration of empty holeboard LTP mechanisms: Induction 1. Why does strong but not weak stimulation induce LTP? a. ... 2. Induction mechanisms: NMDA receptors 1. Some forms of LTP depends on activation of NMDA receptors a. Evidence i. Drugs that block NMDA receptor prevent LTP induction without affecting baseline responses 1. AP5 a. Competitive antagonist 2. MK-801 a. Non-competitive antagonist 3. 7-chlorokynurenic acid a. Glycine antagonist Induction mechanisms: Ca2+ 1. LTP depends on a rise in intracellular calcium concentration a. Evidence i. Drugs that interfere with internal calcium concentrations also block LTP induction 1. Depletion of intracellular Ca2+ stores wiith thapsigargin blocks LTP in CA1 Induction mechanisms: mossy fiber pathway 1. Mossy fiber LTP (DG  CA3) depends on presynaptic increase in intracellular calcium concentration a. i.e. NMDA-independent 2. Instead, mossy fiber LTP induction is dependent on presynaptic kainate GLU receptors LTP mechanisms: expression 1. Presynaptic mechanisms a. Increased probability of neurotransmitter release 2. Postsynaptic mechanisms a. Changes to functional characteristics of synaptic AMPARs b. Insertion of existing AMPARs into the synapse c. Increase in the number of AMPARs by protein synthesis Induction vs Expression LTP mechanisms: Phases of LTP 1. PTP a. Brief (seconds to minutes) b. NMDA independent c. Attributable to transient increase in presynaptic [Ca2+] d. Increased probability of neurotransmitter release 2. STP a. Minutes to 1 hour b. NMDA dependent c. Postsynaptic [Ca2+] dependent 3. E-LTP a. 1-5 hours b. Protein kinase dependent c. Protein synthesis independent 4. L-LTP a. Hours to years b. Protein synthesis dependent 5. Molecular events underlying early and late LTP Expression mechanisms: PTP 1. Post-tetanic potentiation (PTP) a. PTP can be seen even when no further LTP can be induced because of saturation i. The build up of presynaptic Ca2+ concentration during stimulation train 2. Expression mechanisms: early LTP 1. Early LTP (E-LTP)  protein kinase activation (CAMKII, PKC) i. Early LTP is blocked by non-specific protein kinase inhibitory (H-7) 1. PTP and short-term potentiation (STP) are not blocked  AMPAR phosphorylation i. Early LTP may involve changing conductivity of existing AMPARs by phosphorylation of GluA1 subunit  AMPAR insertion i. Approximately 60% of synapses in hippocampal CA1 slices have NMDA receptors with no functional AMPA receptors 1. Renders them postsynaptically silent at hyperpolarized potentials ii. Persistent activation of protein kinases after tetanic stimulations leads to delivery of AMPA receptors to synapses 1. Some of which were previously silent a. i.e. AMPA receptor insertion in 'NMDAR only silent synapses' activates the synapse Expression mechanisms: AMPAR trafficking 1. Tetanic stimulation induces spine delivery and clustering of GFP-labelled GluR1s 2. Expression mechanisms: Late LTP 1. L-LTP a.  Protein synthesis and new RNA transcription i. Requirements for protein synthesis precede transcriptional requirements 1. RNA is present locally, near the dendritic spine. 2. An LTP inducing event will cause protein synthesis to take place at the active spines and set off a cascade of cellular processes that result in transcription of new RNA at nucleus a. Important for an even later phase of LTP ii. Genes with activity regulated transcription are called 'immediate early genes' (e.g. ARC, Homer, BDNF) and can be used as a tool by researchers to identify which cells underwent long term pla
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