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Lecture 7

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Department
Neuroscience
Course
NROC69H3
Professor
Rutsuko Ito
Semester
Fall

Description
Lecture 7 Notes Synaptic plasticity and learning Synaptic plasticity: 1. Activity dependent change in synaptic strength a. Synaptic strength i. The amplitude of the change in membrane potential as a result of presynaptic action potential ii. The strength of a synapse can be accounted for by the number and size of each of the connections from the presynaptic neuron to the postsynaptic neuron iii. The present EPSP magnitude is greatly influenced by prior stimulation 1. Hence synapses show a 'memory' for prior neuronal activity that is encoded by the present synaptic strength 2. Forms of plasticity a. Homosynaptic (non associative) i. Synaptic strength is modulated solely by past activity at that input alone b. Heterosynaptic i. The changes in synaptic strength depend on the timed interaction between two or more synaptic inputs History 1. Donald Hebb a. Proposed that cells that were active (i.e. fired action potentials) at the same time would become more connected to each other compared to cells that were not active at the same time b. Over time, cells would form themselves into 'assemblies' of connected cells to enable information flow c. Hebbian plasticity i. Plasticity that requires simultaneous pre and post synaptic activity ii. Properties to support model of neurocellular mechanism of learning Pavlovian conditioning and Hebbian plasticity 2. Unconditioned stimulus  Unconditioned response a. Unconditioned stimulus + neutral stimulus  unconditioned response i. Neutral stimulus  conditioned stimulus  conditioned response 1. Conditioning said to have occurred 3. Before conditioning a. US activates a strong synaptic circuit controlling the UR b. CS pathway is inactive 4. Pairing of US and CS (initially neutral stimulus) a. Results in EPSP from the weak input followed by an action potential from the strong input i. Coincident presynaptic and postsynaptic action potentials in the weak CS circuit 5. After pairing US and CS (now independent of US) a. CS circuit is strengthened so that its presentation alone can activate the response (UR/CR) 6.  Pavlovian conditioning is an example of temporal pairing of weak and strong inputs in strengthening the weaker input Long term potentiation (LTP) 1. Two forms of heterosynaptic plasticity with Hebbian (associative) properties a. LTP i. High frequency stimulation (HFS) 1. Temporally correlated action potentials in pre and post synaptic neurons can cause a prolonged potentiation of the synaptic strength at glutamatergic synapses (increased fEPSP magnitude) b. LTD i. Low frequency stimulation (LFS) 1. Temporally uncorrelated pre and post synaptic action potentials can cause a prolonged decrease in synaptic strength 2. Synaptic strength a. Measured as the initial slope of the field excitatory postsynaptic potential (fEPSP; normalized to baseline) plotted as a percentage of baseline as a function of time 3. First experiment to show LTP a. Anaesthetized rabbits i. Inserted a stimulating electrode into the axons of the perforant path ii. Inserted a recording electrode into the dentate gyrus iii. Established baseline field potentials with a pulse every 25 s for 20 minutes iv. Alternated a more intense stimulation (15Hz for 15s / 100Hz for 3s) with the baseline pulse (0.5Hz) and recorded the change in field potential b. Result i. After four stimulation trains, the field potential was much larger than at the beginning of the experiment ii.  Intense stimulation of a hippocampal pathway led to a change in synaptic plasticity lasting several hours (tested against control variable) 1. This finding also shown in (some) awake rabbits 4. Three key properties of LTP a. CIA i. Cooperativity 1. A crucial number of presynaptic fibers must be simultaneously activated (cooperate) to elicit LTP ii. Input specificity 1. Only the synapses stimulated from S2 are potentiated iii. Associativity 1. Stimulus trains delivered simultaneously from S1 (weak stimulus) and S2 (strong stimulus) combined such that the weak stimulation from S1 benefitted from the strong stimulation from S2 5. LTP at single synapses a. Studying LTP in pairs of synaptically connected neurons using tissue slices of freshly killed animals Long term depression (LTD) 1. Two forms of heterosynaptic plasticity with Hebbian (associative) properties a. LTP i. High frequency stimulation (HFS) 1. Temporally correlated action potentials in pre and post synaptic neurons can cause a prolonged potentiation of the synaptic strength at glutamatergic synapses (increased fEPSP magnitude) b. LTD i. Low frequency stimulation (LFS) 1. Temporally uncorrelated pre and post synaptic action potentials can cause a prolonged decrease in synaptic strength 1. LTD a. Sustained reduction in field potential size in response to prolonged low frequency stimulation i. Opposite of LTP -- reducing the connection between two brain regions or pairs of cells 2. Functional significance of LTD a. Plays a role in enhancing signal to noise ratio b. Acts as a forgetting mechanism c. Means of erasing stored information d. Learning mechanism? 3. Study a. Novelty exploration can induce different types of synaptic plasticity in CA1 b. 1) Animals explored a novel holeboard with novel objects concurrent with a sub- threshold low frequency stimulation (LFS) i. Led to faciltation of LTD c. 2) After 8-10 days, the experiment was repeated i. This time, no exploratory induced change took place in LFS-elicited fEPSP depression d. 3) Familiar objects put in wholes in a different configuration (novel object configuration) i. Enough to trigger a facilitation of LTD similar to that triggered by the complete novel experience of the first experiment e. Conclusion i. 1) Novel exploration led to facilitation of LTD ii. 2) When animals were familiar with the holeboard and objects, exploration did not change synaptic weights in CA1 iii. 3) Novel information driving the induction of LTD in CA1 is the association between a place and an object 1. However, novel exploration is not always correlated with LTD a. Having an empty holeboard (with no objects) did not facilitate LTD iv. Implications for spatial learning in the sense of encoding a new complex environment 1. Involves bidirectional changes in synaptic weights LTP mechanisms 1. Properties of LTP induction a. Opening of postsynaptic NMDA type glutamate receptors i. Drugs that block NMDA receptor function (AP5 / MK801 / 7-chlorokynurenic) prevent LTP induction without affecting baseline responses b. Most active glutamatergic synapses express both AMPA and NMDA receptors i. A low frequencies of presynaptic stimulation 1. Fast glutamatergic EPSPs are mediated largely by AMPA receptors a. NMDA receptors make only a small contribution to fast EPSP i. Activation requires both glutamate binding (presynaptically released) and a relatively large postsynaptic depolarization ii. The necessary 'large' postsynaptic depolarization is induced by AMPA receptor activation during high frequency stimulation b. NMDA receptor = molecular coincidence detector i. After HFS (high frequency stimulation) 1. The AMPA receptor mediated EPSPs are potentiated and make remain so for several hours c. Calcium influx that occurs through the open NMDA receptor channels i. Drugs that interfere with the rapid rise in intracellular calcium channels also block LTP induction ii. Postsynaptic calcium influx triggers the activation of a complex kinase signaling pathway that leads ultimately to increase AMPA receptor channel conductance and a greater number of postsynaptic AMPA receptor channels 1. The NMDA receptor response may also be enhanced a. This is important because changes in basal NMDA currents can alter the induction threshold for subsequent synaptic plasticity (metaplasticity) i. However, there are also NMDA independent forms of LTP (less common) 1. E.g. Mossy fiber pathway LTP depends on a. Intracellular rise in Ca2+ b. Activation of presynaptic kainate receptors 2. LTP expression a. Has a number of temporal phases that rely on different cellular mechanisms i. Post-tetanic potentiation (PTP) 1. Brief (seconds to minutes) 2. NMDA independent 3. Attributable to a. Transient increase in presynaptic [Ca2+] b. Increased probability of neurotransmitter release 4. PTP can be seen even when no further LTP can be seen due to saturation a. The build up of presynaptic [Ca2+] concentration during a stimulus train ii. Short term potentiation (STP) 1. Minutes to hours 2. NMDAR dependent 3. Dependent on presynaptic Ca2+ concentration duri
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