LONG-TERM POTENTIATION (LTP)

  1. Introduction
    1. LTP as a candidate mechanism for the activity-dependent change in the strength of synaptic connections
    2. LTP is a persistent increase in synaptic strength (as measured by the amplitude of the EPSP) that can be rapidly induced by brief neural activity.
  2. Anatomical background
    1. Hippocampal formation consists of two interlocking C-shaped regions (the hippocampus and the dentate gurus), see Fig. 4-1, 4-2
    2. main inputs to the hippocampal formation come from the nearby entorhinal cortex via axon of the perforant pathway that push through ("perforate") the subculum
    3. Hippocampus has three major afferent pathways (subiculum -> CA1), see Fig. 4-3
      1. Perforant pathway (subiculum -> granule cells in dentate gyrus)
      2. Mossy fiber pathway (axons of the granule cells -> pyramidal cells in the CA3)
      3. Schaffer collaterals (pyramidal cells in the CA3 -> pyramidal cells in the CA1)
  3. The initial finding by Timothy Bliss and Terje Lomo (1973)
    1. Anaesthetized rabbit
    2. Brief, high-frequency stimulation of the perforant pathway input to the dentate gyrus produced a long lasting enhancement of the extracellular recorded field potential.
  4. LTP has been observed in other parts of the nervous system
    1. Mammalian neocortical regions, subcortical nuclei
    2. Mammalian peripheral nervous system
    3. Invertebrate
  5. Experimental design, see Fig. 4-4
    1. Stimulation of a bundle of presynaptic axons
    2. recording of monosynaptic EPSP
  6. Recording techniques
    1. In vivo (in awake and freely moving animals, or in anesthetized animals)
    2. in vitro (slice preparations)
    3. Extracellar recordings
    4. intracellular recordings
  7. Typical results for induction of LTP, see Fig. 4-5, 4-6
  8. The "classical properties" of LTP, see Fig. 4-7
    1. Cooperativity
      1. The probability of inducing LTP, or the magnitude of the resulting change, increases with the number of stimulated afferents.
    2. Associativity, see Fig. 4-8, 4-9
      1. associativity was shown in preparations in which two distinct axonal inputs converged onto the same postsynaptic target
      2. Concurrent stimulation of weak and strong synapses to a given neuron strengthens the weak ones.
    3. Input specificity, see Fig. 4-9
      1. LTP is restricted to only the inputs that received the tenanic (high-frequency) stimulation
  9. Hebbian mechanism
    1. "when an axon of cell A ... 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 such that A's efficiency, as one of the cells firing B, is increased" (Hebb, 1949)
  10. Underlying molecular mechanisms
    1. Introduction
      1. LTP requires some sort of additive effect
        1. High-frequency stimulation
      2. Activation of synapses and depolarization of the postsynaptic neuron must occur at the same time
    2. LTP (in area CA1) depends on certain changes at glutamate synapses, see Fig. 4-10 or 4-11
    3. Types of glutamate receptors
      1. NMDA receptors
      2. Non-NMDA receptors
    4. At non-NMDA receptors,
      1. glutamate is excitatory
      2. Open channels for sodium ions
    5. At NMDA receptors,
      1. Controls a calcium ion channel
      2. glutamate is neither excitatory nor inhibitory
      3. Ion channel is blocked by magnesium ions
      4. Activation of NMDA receptors requires both glutamate and depolarization, which lead to the removal of magnesium ions
      5. The NMDA receptors now respond actively to glutamate and admit large amount of Ca2+ through their channels
      6. After induction of LTP, transmission at non-NMDA receptors is facilitated
    6. Opioid peptides modulate the induction of LTP in the CA3 region
    7. LTP is induced via a cascade of neurochemical steps, see Fig. 4-12
      1. The entry of Ca2+ ions into neurons activates some protein kinases (which are enzymes that catalyze phosphorylation, the addition of phosphate groups to protein molecules).
      2. One of the kinase, Calcium-calmodulin kinase (CaM kinase) remains activated once it is put into that state by Ca2+, even if the level of Ca2+ subsequently falls
      3. The activated protein kinases also trigger the synthesis of proteins
        1. activate cAMP responsive element-binding protein (CREB)
        2. CREB -> production of the transcription (mRNA) of immediate early genes (IEGs) -> regulate the expression of particular late effector genes (LEGs) -> synthesis of proteins
      4. Induction of LTP requires a retrograde signal, from the postsynaptic neuron to the presynaptic neuron


LONG TERM DEPRESSION (LTD)

  1. Definition: a lasting decrease in the magnitude of responses of neurons after afferent cells have been activated with electrical stimuli of relatively low frequency
  2. Dudek and Bear (1992) stimulated Schaffer collateral inputs to CA1 neurons in hippocampal slices with 900 pulses of electrical current.
    1. Frequencies > 10 Hz -----> LTP, see Fig. 4-12b
    2. Frequencies < 10 Hz -----> LTD, see Fig. 4-12b
    3. both of these effects require NMDA receptors
  3. Stanton and Sejnowski (1989) demonstrated associative LTD in field CA1.
    1. A weak input was paired with a strong input ----> LTP
    2. The two inputs were stimulated at different times ----> LTD
  4. Thus Hebb rule appears to work in both directions
    1. Input correlated with strong inputs (or with activation of the postsynaptic neuron) are strengthened
    2. Input not correlated with strong inputs (or with nonactivation of the postsynaptic neuron) are weakened
    3. This mechanism could conceivably allow for the reversal of previously established synaptic changes when the contingencies in the environment change.
  5. In CA1region induction of LTD require the entry of Ca2+, through NMDA receptors, see Fig. 4-12c
    1. Large amount of Ca2+ --> activate protein kinases --> LTP
    2. Small amount of Ca2+ --> activate protein phosphatases --> LTD