Excitotoxicity

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  • The term "excitotoxicity" is used to describe the process by which neurons are damaged by glutamate and other similar substances.
  • Excitotoxicity results from the overactivation of excitatory receptor activation.

The Mechanism of Excitotoxicity

  • Glutamate is the major excitatory transmitter in the brain and spinal cord.
    • There are four classes of postsynaptic glutamate receptors for glutamate.
      • The receptors are either:
        • Directly or indirectly associated with gated ion channels, OR
        • Activators of second messenger systems that result in release of calcium from intracellular stores.
      • The receptors are named according to their phamacological agonists:
        • NMDA receptor
          • The NMDA receptor is directly linked to a gated ion channel.
          • The ion channel is permeable to Ca++, as well as Na+ and K+.
          • The channel is also voltage dependent.
            • It is blocked in the resting state by extracellular Mg++, which is removed when membrane is depolarised.
          • I.e. both glutamate and depolarisation are needed to open the channel.
        • AMPA receptor
          • The AMPA receptor is directly linked to a gated ion channel.
          • The channel is permeable to Na+ and K+ but NOT to divalent cations.
          • The receptor binds the glutamate agonist, AMPA, but is not affected by NMDA.
          • The receptor probably underlies fast excitatory transmission at glutamatergic synapses.
        • Kainate receptor
          • Kainate receptors work in the same way as AMPA receptors, and also contribute to fast excitatory transmission.
        • mGluR, the metabotropic receptor
          • Metabotropic receptors are indirectly linked to a channel permeable to Na+ and K+.
          • They also activate a phoshoinositide-linked second messenger system, leading to mobilisation of intra-cellular Ca++ stores.
          • The physiological role ot mGluR is not understood.
  • Under normal circumstances, a series of glutamate transporters rapidly clear glutamate from the extracellular space.
    • Some of these transporters are neuronal; others are found on astrocytes.
  • This normal homeostatic mechanism fails under a variety of conditions, such as ischaemia and glucose deprivation.
    • This results in a rise in extracellular glutamate, causing activation of the neuronal glutamate receptors.
  • Two distinct events of excitiotoxicity arise from glutamate receptor activation:
    1. The depolarisation caused mediates an influx of Na+, Cl- and water. This give acute neuronal swelling, which is reversible.
    2. There is a rise in intracellular Ca++.
      • This is due to:
        • Excessive direct Ca++ influx via the NMDA receptor-linked channels
        • Ca++ influx through voltage gated calcium channels following depolarisation of the neuron via non-NDMA receptors
        • Release of Ca++ from intracellular stores.
      • The rise in neuronal intracellular Ca2+ serves to:
        • Uncouple mitochondrial electron transport and activate nitric oxide synthase and phospholipase A, leading to generation of reactive oxygen and nitrogen species which damage the neurone.
        • Activats a number of enzymes, including phospholipases, endonucleases, and proteases.
          • These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.
  • Excitotoxicity is, therefore, a cause of acute neuron death.