Synaptic Plasticity

Synaptic Plasticity

Rachel Jackson from the Centre for Developmental Neurobiology discusses synaptic plasticity, its mechanisms, and its role in neurodevelopmental and neurodegenerative diseases.

Learning Outcomes

By the end of this session, you should:

  • Know what synaptic plasticity is.
  • Understand some of the key mechanisms.
  • Understand how synaptic plasticity relates to neurodevelopmental and neurodegenerative diseases.
  • Discuss specific examples in these disorders.

Synapse Recap

  • Dendrites: Input to the neuron.
  • Cell Body: Main part of the neuron.
  • Axon: Output of the neuron.
  • Synapse: The junction where the axon of one cell meets the dendrite of another.
  • Excitatory Synapses: Typically form onto spines, which are protrusions from the dendrites.
  • Postsynaptic Density: A protein-rich area on the postsynaptic side containing receptors for neurotransmitters.
  • Active Zone: An area on the presynaptic side where the release machinery is located.

Synaptic Transmission

  1. An action potential arrives at the presynaptic bouton.
  2. Voltage-gated calcium channels open, triggering the release of neurotransmitter-filled vesicles.
  3. Release Probability: The likelihood of a synapse releasing neurotransmitter in response to an action potential; varies across synapses.
  4. Neurotransmitters diffuse across the synaptic cleft and bind to receptors on the postsynaptic cell.
  5. Ion entry causes depolarization, changing the membrane voltage.
  6. In excitatory synapses, this depolarization can lead to the postsynaptic cell firing an action potential, transferring information.

Synapse Variability

Synapses vary in size and properties. EM reconstructions show differences in bouton volume, active zone area, and postsynaptic density size.

  • Bouton Volume: Varies across synapses.
  • Active Zone Area: Varies in size.
  • Spine Volume: Postsynaptic density also varies in volume.

Release Probability

Many boutons have a low release probability.

Postsynaptic Current

  • Measured by stimulating spines with glutamate and observing depolarization.
  • Spines show varying responses to glutamate stimulation.

Correlation of Structure and Function

  • Larger boutons have a higher release probability.
  • Active zone area strongly correlates with release probability.
  • Larger spines have a larger postsynaptic current.
  • Spine volume correlates with the size of the current (number of receptors).

Synaptic Plasticity Definition

Synaptic plasticity is the ability of synapses to change their strength in response to prior activity. This involves changes in synapse structure, function, or both.

  • Occurs on a large scale during nervous system development.
  • Ongoing throughout life.
  • Underlies learning and memory.

Types of Plasticity

  • Short-Term Plasticity: Millisecond to second timescale.
  • Long-Term Plasticity: Lasts hours or years.

Long-Term Potentiation (LTP)

First discovered in the 1970s in the hippocampus (involved in working and spatial memory).

  • Experiment:
    • A slice preparation is made ex vivo.
    • A recording electrode is placed in a neuron.
    • Stimulating electrodes stimulate two different inputs to that neuron.
    • A test pulse determines connection strength.
    • A strong, high-frequency (tetanic) stimulus is delivered to one input.
    • The test pulse is repeated to see if the connection strength has changed.
  • Result:
    • The input that received high-frequency stimulation shows a massively increased response.
    • The unstimulated input shows no change.
  • Input-Specific: Only the stimulated input is strengthened.

Hebb's Postulate (1949)

"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 the efficiency of one of the cells firing B is increased."

  • Key Point: The postsynaptic cell (cell B) must be firing for the strengthening to occur.
  • Simplified: "Cells that fire together wire together."
  • Hebbian Plasticity: Plasticity that follows Hebb's postulate.

Mechanism for Detecting Correlation

The postsynaptic cell uses glutamate receptors to detect the correlation between presynaptic neurotransmitter release and postsynaptic firing.

  • Glutamate Receptors:
    • AMPA receptors
    • NMDA receptors
  • NMDA Receptor Block: At rest, NMDA receptors are blocked by a magnesium ion (Mg^{2+}).
  • Depolarization: The \Mg^{2+} block is relieved when the cell is depolarized.
  • Weakly Active Synapse:
    • Small amount of glutamate released.
    • AMPA receptors open and allow some sodium (Na^+) in, but not enough for significant depolarization.
    • The \Mg^{2+} block remains on NMDA receptors.
  • Strongly Stimulated Presynaptic Cell:
    • More glutamate released.
    • More receptors bind glutamate, increasing ion influx.
    • Large depolarization occurs, relieving the \Mg^{2+} block on NMDA receptors.
    • Calcium ions (Ca^{2+}) enter through NMDA receptors.
  • Calcium Importance:
    • Ca^{2+} ions act on downstream pathways, leading to LTP.
    • While some AMPA receptors might allow Ca^{2+} the pore structure of most AMPA receptors primarily allows Na^+, and potassium (K^+$​) ions to pass through.

Long-Term Depression (LTD)

An opposite effect to LTP, where connections between inputs and cells are weakened.

  • Experiment: Similar setup to LTP experiments with recording and stimulating electrodes.
  • Stimulation: Low-frequency stimulation induces a decrease in synaptic response.
  • Result: Synaptic response decreases to 60-70% of the original strength.
  • Input-Specific: Only the stimulated input is weakened.

LTD and Receptors

  • LTD can involve NMDA receptors, based on calcium (Ca^{2+}$$) influx levels.
  • Can also involve other glutamate receptors, like mGluRs.
  • Different activity types can cause output LTD.

Timing of Activity

  • Pre before Post (Positive Timing):
    • Presynaptic cell fires before postsynaptic cell.
    • Implies presynaptic firing causes postsynaptic firing.
    • Results in LTP.
  • Post before Pre (Negative Timing):
    • Postsynaptic cell fires before presynaptic cell.
    • Implies presynaptic firing is not causing postsynaptic firing.
    • Results in LTD.

How Synapses Change Strength

  • Baseline Synapse: Contains NMDA and AMPA receptors.
  • High-Frequency Stimulation (LTP):
    • More AMPA receptors are inserted into the membrane.
    • Spine gets larger.
  • LTD:
    • AMPA receptors are internalized (removed from the surface).
    • Spine gets smaller.
  • Postsynaptic Side: Changes in receptor number affect the synapse's responsiveness to glutamate.
  • Presynaptic Side: Can end up with a larger active zone and a higher release probability, further strengthening the connection.

Structural Plasticity

LTD can lead to the complete removal of synapses. Synapses can be lost and gained.

Example Experiment in Adult Mice

  • Whiskers trimmed or small lesion on the retina.
  • Looked at the barrel cortex or visual cortex, respectively.
  • Cortical neurons experienced low activity due to sensory deprivation.
  • Spines are fluorescently labeled.
  • Results:
    • Spines are generally stable.
    • Some spines form (orange).
    • Some spines are removed (green).
    • Some spines are transient (form and disappear).
    • After sensory deprivation, more new spines form, and old spines don't survive as long.
    • Spine density remains the same overall (stability).

Synaptic Plasticity, Human Studies, and Development

  • Synaptic plasticity as a potential target for areas where it's disruptive.
  • Evidence of structural synaptic plasticity in humans
    • London taxi drivers have larger hippocampi due to spatial navigation demands.
    • Medical students' brains show changes during exam preparation.
  • During the development of the nervous system
    • Loss and gain of synapses and changes in connectivity.
    • Remodeling of dendritic arbors and axons

Experiment Showing Connectivity Changes (1960s)

  • Visual cortex study.
  • Neurons from the retina project to the visual cortex from both the ipsilateral (same side) and contralateral (opposite side) eyes.
  • Neurons responding to the same eye group together in columns.
  • Monocular Deprivation: Suturing one eye shut during early development.
  • Result: Neurons from the open eye take over territory, and neurons from the closed eye reduce.
  • Axon Changes: Axons from the non-deprived eye are larger and more branched, forming more synapses. Axons from the deprived eye are smaller with less branching and fewer synapses.

Synapse Pruning in Development

  • In humans, synapses form before birth and continue until around age two (or later in some cortical areas).
  • Gradual decline of synapses occurs, refining the nervous system.
  • This pruning process occurs until around 20-30 years of age, then synapse number remains stable until age-related synaptic loss.
  • LTD could be a mechanism for removing synapses.

Neurodevelopmental Disorders

  • Synapse development occurs during early life, when neurodevelopmental disorders (ASD, epilepsy, intellectual disability) often onset.
  • Later-onset disorders (schizophrenia, bipolar disorders) manifest in adolescence during spine pruning.
  • Genetic changes in ASD patients often involve postsynaptic and presynaptic proteins.
  • ASD patients have increased spine density, suggesting a failure to prune.

Syndromic Forms of Autism

  • Fragile X Syndrome: Caused by a single gene mutation; leads to increased spine density and turnover in mice.
  • Tuberous Sclerosis Complex (TSC): Patients exhibit autism symptoms and seizures; TSC1 knockout mice show increased spine density.
  • Synaptic plasticity must operate within an optimal window. Too much or too little plasticity can cause similar phenotypes.

Schizophrenia

  • Genetic risk factors involve NMDA receptor signaling and proteins downstream of AMPA and NMDA receptors.
  • Schizophrenia is associated with decreased spine density.
  • Neurexin 1, a protein encoded by a schizophrenia risk gene, affects LTP when its levels are altered.
  • Neurodevelopmental disorders can result from changes in synapse formation, plasticity, and pruning that overall result in changes in the synapse number.
  • In ASD, there's increased synapse formation and a failure to prune, leading to increased spine density.
  • In schizophrenia, initial synapse formation is normal, but excessive pruning results in fewer synapses.
  • Modulating plasticity directionally can lead to similar phenotypes, so different targets might be needed to push phenotypes back towards wild type.

Neurodegenerative Diseases (Alzheimer's Disease)

  • Synapses and neurons are progressively lost.
  • Synapse loss correlates strongly with cognitive impairment.
  • Adding soluble A-beta oligomers (toxic species in AD) to hippocampal slices decreases LTP and increases LTD in mice.
  • Synapse number decreases.

Chronic Pain

  • Involves the anterior cingulate cortex (ACC), important for pain perception.
  • Rats with an amputated digit show increased LTP and decreased LTD in ACC neurons.
  • Overall level of neurotransmission increased.
  • Plasticity is needed for brain function, but chronic pain may result from an overactive system.

Downstream Targets

  • Calcium-stimulated adenylate cyclase 1 (AC1) found to be involved in the enhanced LTP.
  • Blocking AC1 prevents LTP in controls.
  • AC1 blocker (NB001) reduces chronic pain responses in animals without affecting acute pain.

Synapse Strength Seesaw

  • Alzheimer's Disease: Less strengthening (less LTP) and more weakening (more LTD), leading to weaker synapses and synapse loss.
  • Chronic Pain: More strengthening (more LTP) and less weakening (less LTD), leading to stronger synapses.