Mechanisms of Synaptic Plasticity

Hippocampus
1. located within the medial temporal lobe of the brain. It forms part of the limbic system
2. Hippocampal Pathways
3. Hippocampal Function
  1. CA1 region of the hippocampus is vital for some forms of learning
  2. Hippocampus is responsible for the acquisition of memory with particular emphasis on spatial memory
    1. maintains a neural representation of spatial environment
Presynaptic mechanisms of plasticity
1. Short-term Plasticity
  1. 3 types of Short-term plasticity
    1. Paired Pulse Depression
      1. Synapses that release transmitter at a high release probability
      2. 3 factors for reduced release
        Depletion of the proportion of vesicles that are in the Readily Releasable Pool (RRP)
        Release site innactivation due to vesicular membrane proteins interfering with membrane consistency/ protein interactions
        Decreased calcium influx. Decreased activity of Ca/ Calmodulin complex. P-type Ca Channels not activated
    2. Paired Pulse Potentiation
    3. Paired Pulse Facilitation
      1. Hippocampal mossy fibres participate in a lot of PPF at the synapse to CA3 Pyramidal cells.
        Low Release probability
        Metabotropic receptors are the "brakes" the cell applies to ensure that there is a limit to the magnitude of frequency-dependent facillitation
        Fibres contain adenosine A1 GPCRs on the presynaptic cell. These receptors have an inhibitory effect on glutamate release
        Mossy fibres also express metabatropic Glutamate receptors (mGluR 2 or 3) which also suppress glutamate release at the synapse by inhibiting calcium entry
        negative feedback to stop over excitation/ glutamate release as Glutamate spills over to activate mGluR
        Activation of G protein-coupled receptors can transiently inhibit vesicular release through the release of Gβγ which binds to both voltage-dependent calcium channels to reduce calcium influx, and directly to the C-terminus region of the SNARE protein SNAP-25
    4. Pairs of pulses delivered at intervals of several tens of milliseconds
  2. Unlike LTD or LTP, the effects last for a maximum of a couple of seconds
  3. Calcium dependency
    1. Short-term facilitation
    2. Transmitter release
      1. Transient increases in [Ca2+]i, in close proximity to voltage-gated Ca channels, drive phasic transmitter release. This contributes to depolarisation
        Ca2+ channels will remain open until repolarisation occurs
        Calcium signal will reduce quickly due to diffusion
        Residual Calcium signals remain (at a concentration of ~500nM) as Calcuim buffering and extrusion (active transport out of the cell or into intracellular stores) are slow therefore there is a slow signal decay
        Residual calcium builds up during repetitive stimulation (5-10Hz)
        Asynchronous signalling
        Synchrony
        Residual calcium may serve as a mechanism for short-term plasticity within neuronal circuits
        [Ca2+] levels in the tens of micromolar range
      2. Mechanism of transmitter release
        How many molecules of Ca2+ are needed for Synaptotagmin to perform vesicular exocytosis??
        Ca sensitive protein which, when bound to embedded proteins, forms the SNARE complex
        2 models
        5-site
        Does not account for the calcuim concentration range at which exocytosis of vesicles occurs
        may therefore require activation at an allosteric site in low calcium concentrations
        2-site 5-site
        2-site filled
        Possible at low concentrations of calcium, slow calcium sensor
        Asynchronous
        5-site filled
        only possible at high concentrations, fast calcium sensor
        Synchronus
    3. Synchrony
2. Long-term
  1. mGluR may also have a long-term presynaptic effect
    1. Activation of G protein-coupled receptors can transiently inhibit vesicular release through the release of Gβγ which binds to both voltage-dependent calcium channels to reduce calcium influx, and directly to the C-terminus region of the SNARE protein SNAP-25.
      1. Alford et al. 2013 showed that it is necessary but not sufficient to produce LTD alone
  2. Presynaptic LTP in the Mossy fibre/ CA3 pyramidal synapse
    1. Increases in PRESYNAPTIC Calcium
      1. post-synaptic calcium has a very small role
      2. N-type, P/Q-type and R-type Calcium Channels have all been implemented as important for calcium entry
        N or P/Q type are sufficient for LTP induction
        Access to AC and release machinery
        R-type channels
        Lower threshold for LTP induction
        Does not have access to the release machinery
        Preferential access to Adenylyl Cyclase (AC)
        Through Calmodulin/Ca complex
        Amplitude of EPSP does not change significantly between WT and mice with a R-type subunit knockout
        Enhancement of neurotransmitter release involves enhanced Ca coupling to SNARE complex
Post synaptic Mechanisms of Plasticity
1. Long Term Potentiation (LTP)
  1. Molecular mechanisms of long-term potentiation
    1. Signalling Cascades
      1. Increased [Ca2+]i allows for Calmodulin to bind 4Ca2+ cations
        Ca/Calmodulin complex activates CAMKII (Cacium/calmodulin kinase 2) ***
        Ca/Calmodulin complex also activates membrane-bound Adenylyl Cyclase
        ATP > cAMP
        cAMP bind and activates Phosphokinase A (PKA)
        PKA traslocates into the nucleus
        Kinases Activate CREB1 (cAMP response element binding protein)
        CREB activates CRE (cAMP response element)
        Calcium-regulated gene expression of certain growth factors that may enable De novo spine formation
        PKA can also activate MAPK (mitogen activated protein kinase)
        MAPK translocates into the nucleus
    2. Signal transduction
      1. NMDA receptors
        NMDA receptors open with Glutamate binding on the extracellular domain.
        "coincidence detectors" as require Mg block removal and glutamate
        Influx of Ca2+, Na+ and efflux of K+
        Intracellular Ca2+ increases with opening of NMDA channels
      2. AMPA Receptors
        On ligand (aglutamate) binding, AMPA receptors open, allowing for sodium influx and potassium eflux
        Intracellular concentrations of Na are higher than external concentrations. The net possitive charge intracellularly resultis in the magnesium block in NMDA channels to be removed
        Increased [Ca2+]i allows for the Ca/Calmodulin complex to form
        Ca/Calmodulin activates CAMKII by phosphorylation ***
        CAMKII phosphorylates Stargazin scaffold protein
        PSD95 can therefore bind and can relocate the AMPA receptor to the post-synaptic density
        CAMKII also phosphorylates the GluR1 subunit at Serine 831
        Increases the Conductance of the AMPA Receptor
  2. How is LTP induced?
    1. Pyramidal neurons fire at a frequency of 5Hz. This is known as "theta rhythm"
      1. Theta rhythm
        Three trains of stimuli that are 20 seconds apart
        Each train composed of 10 stimulus epochs which are delivered at 5Hz (i.e. 200ms apart)
        each epoch is made up of four individual stimuli at 100Hz
      2. during exploration (spatial mapping)
  3. Discovery
    1. Raising the frequency of firin from 0.5Hz to 15Hz
      1. follow grey lines
        Baseline at 0.5 Hz
        Initial facilitation of EPSP at 15 Hz
        Rapid decline past baseline
        Gradual rise to an increased baseline mV
  4. Properties
    1. 4 major properties/ conditions neccessary for LTP
      1. Cooperativity
        LTP can be induced by a single, strong, tetanic signal to a synapse OR via weaker stimulation of may cooperating pathways
      2. Associativity
        the contributing fibres need to be active together
        information from the two contributing sources must coincide both temporally and spatially
        Weak tetanic stimulus in one location will be insufficient in producing LTP, but paired with a strong signal in another location can induce LTP
      3. Input specificty
        LTP will only occur at synapses which receive tetanic stimulation, even if it is within the same cell, other synapses which do not recieve stimulation will not share in synaptic enhancement (i.e. increased expression of AMPA or NMDA receptors)
      4. Persistance
        LTP is also persistent, it can last for several hours and even for many months suggesting that a sustained physiological change accompanies memory formation
  5. 'Hebb Rule' = if both pre and post-synaptic cell are excited at the same time, the synaptic connection is strengthened
2. Glutamate is the main excitatory neurotransmitter in the synaptic transmission between Schaffer Collateral fibres and the CA1 pyramidal cells

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	Criado por Catherine Salmon mais de 9 anos atrás