Excitotoxicity

• 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.