Synaptic plasticityhippocampus. Neur 8790 Topics in Neuroscience: Neuroplasticity. Outline. Synaptic plasticity hypothesis

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1 Synaptic plasticityhippocampus Neur 8790 Topics in Neuroscience: Neuroplasticity Outline Synaptic plasticity hypothesis Long term potentiation in the hippocampus How it s measured What it looks like Mechanisms 1

2 Synaptic plasticity Synaptic strength Ease with which cell A can excite or inhibit cell B Synaptic plasticity Synaptic strength is not fixed- is modifiable Means by which experience can produce persistent changes in the brain Vs. neuron number Donald Hebb Hebb s postulate: When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A s efficiency, as one of the cells firing B, is increased. Hebbian synapse: theoretical connections among neurons that strengthen as a result of activity 2

3 Memory: strengthen synaptic connections that link neuronal populations Learning experience Retrieving the trace Long-term potentiation (LTP) The leading candidate cellular mechanism of memory 3

4 Understanding Field Potentials In many studies of LTP, the dependent variable is called the Field Excitatory Postsynaptic Potential AKA Field EPSP (fepsp) AKA population response. Critical to understand how it is measured and why it is thought to represent synaptic strength. Review synaptic transmission & PSPs Postsynaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the postsynaptic cell 4

5 The membrane potential Extracellular intracellular The membrane potential 5

6 6

7 fepsp & Synaptic Strength fepsp the rate at which positive ions are flowing away from the extracellular recording electrode. Assumed these positive ions are entering the postsynaptic neuron and depolarizing the slope of the fepsp indirectly measure the strength of the synaptic connections near the electrode. mv 70 Recording Electrode time Reference Electrode 7

8 mv Recording Electrode 70 time Reference Electrode 8

9 Long-term Potentiation An enduring (>1 hour) increase in synaptic efficacy that typically results from highfrequency stimulation of an afferent (input) pathway i.e., cellular memory, support for Hebb s postulate Synaptic connections in the hippocampus 9

10 Bliss and Lomo s experimental design: Stimulate a bundle of presynaptic axons Perforant path Use extracellular recording electrode to measure monosynaptic fepsp Dentate gyrus Record fepsp before and after high frequency stimulation Tetanic stimulation: brief burst of high frequency stimulation ( stimuli at 100/sec) Increase in fepsp indicates potentiation Choosing the test and inducing stimuli 10

11 Define arrows 2 functions of test stimulus establishes a baseline, used to determine if the inducing stimulus produced LTP. 11

12 Remove hippocampus from brain and keep alive in a dish Observe cells, stimulate and record Allows study of plasticity in vertebrates Confirms Bliss & Lomo In vitro brain slice preparation Evidence of LTP Extracellular recordings more cells fire after tetanus Intracellular recordings individual cells have increased EPSPs more easily reach threshold for firing 12

13 Properties of LTP in CA1 Pairing Presynaptic and Postsynaptic Activity Causes LTP or STIM 13

14 The Chemical Basis of LTP: Ionotropic Glutamate Receptors glutamate released by the presynaptic neuron acts at 3 receptor subtypes on dendrites of postsynaptic neurons non-nmda receptors dominate in normal synaptic transmission Three types of glutamate receptors 14

15 Blocking NMDARs prevents induction but not expression What is special about NMDA receptors? 15

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17 NMDA receptors are Hebbian coincidence detectors Double-gated Ligand-gated requires glutamate binding Signals presynaptic activity Voltage-gated requires depolarization to remove magnesium from the channel pore Signals postsynaptic activity Calcium is a signal that both the presynaptic neuron (glutamate) and postsynaptic neuron (depolarization) are active What produces the postsynaptic depolarization? activation of many AMPA receptors opened by the firing of the presynaptic neurons during tetanic stimulation glutamate opens AMPA temporal and spatial summation of EPSPs 17

18 Blocking AMPARs prevents induction & expression Steps involved in LTP induction 18

19 Second messengers First messengers: between neurons Second messengers: within the neuron Kinases Are Targets of Calcium and Calmodulin 19

20 CAMKII increases AMPA activity AMPA receptor conformation Allow larger influx of Na Move AMPA receptors from silent synapses Increase contribution to the synaptic response AMPA receptor trafficking between membrane & cytoplasm Increase contribution to the synaptic response Several P sites regulate AMPA function The GluR1 subunit has three phosphorylation sites represented as P1, P2, and P3. Each site is phosphorylated by a different kinase. The phosphorylation of each site regulates a different function. 20

21 Cytoskeletal changes also contribute to insertion of AMPARs Actin filaments are rearranged to broaden spines 21

22 LTP Phases Induction AMPA-dependent: produce sufficient depolarization NMDA-dependent: allow Ca entry into postsynaptic cell Maintenance & expression AMPA-dependent: trafficking, conductance, cytoskeleton LTP Early Phase (ELTP) Protein kinase activation and protein phosphorylation LTP Late Phase (LLTP) Protein synthesis from existing mrna and from gene expression LTP depends on stimulus used to induce it Long-lasting (L)-LTP induced by strong highfrequency stimulation depends on transcription processes that generate new mrnas translation processes that synthesize new proteins. Short-lasting (S)-LTP induced by relatively weak high-frequency stimulation Ca, protein kinases, 22

23 Protein synthesis is required for L-LTP Transcription (In the Nucleus) & Translation (Outside the Nucleus) Transcription: a portion of DNA is converted into RNA in the nucleus Protein synthesis: ribosomes translate mrna into protein 23

24 Genes Transcribed by CREB are Important for L-LTP but not S-LTP Field EPSP (% of Baseline) Con CREB KO Time (mins) Synaptic activity induces translation of mrna already present- not new mrna 24

25 Parallel effects of synaptic activity produce L-LTP Local translation Existing mrna Genomic cascade New mrna Two waves of protein synthesis important for L-LTP 25

26 What proteins (plasticity products PPs) are made? CaMKII GluR1/2 subunits/ampa receptors Proteins that facilitate transport of other proteins e.g. eukaryotic elongation factor 1A (eef1a) Cytoskeletal proteins e.g., integrins 26