Excitotoxicity in neurological disorders — the glutamate paradox

Abstract

Beneficial effects of glutamate-receptor antagonists in models of neurological disorders are often used to support the notion that endogenous excitotoxicity (i.e. resulting from extracellular accumulation of endogenous glutamate) is a major contributor to neuronal death associated with these conditions. However, this interpretation conflicts with a number of robust and important experimental evidence. Here, emphasis is placed on two key elements: (i) very high extracellular levels of glutamate must be reached to initiate neuronal death, far above those measured in models of neurological disorders; and (ii) changes in extracellular glutamate as measured by microdialysis are not related to changes in the synaptic cleft, i.e. the compartment where neurotransmitter glutamate interacts with its receptors. It has become clear that the diversity and complexity of glutamate-mediated processes allow for a wide range of potential abnormalities (e.g. loss of selectivity of glutamate-operated ion channels, abnormal modulation of glutamate receptors). In addition, as neuronal death subsequent to ischemia and other insults is likely to result from multifactorial processes that may be inter-related, inhibition of glutamate-mediated synaptic transmission may be neuroprotective by increasing the resistance of neurons to other deleterious mechanisms (e.g. inadequate energy supply) that are not directly related to glutamatergic transmission.

Phosphene perception is due to the ultra-weak photon emission produced in various parts of the visual system: glutamate in the focus

“…stroke and anoxia). Obrenovitch et al (2000) suggested that glutamate neurotoxicity is a multifactorial process and glutamate neurotoxicity is not directly related to glutamatergic transmission but to inadequate energy supply (i.e. a mitochondrial dysfunction).…”

Glutamate-related gene expression changes with age in the mouse auditory midbrain

“…However, neuronal over-stimulation by glutamate is responsible for both acute (McEwen and Magarinos, 1997;Akins and Atkinson, 2002) and chronic (Coyle and Puttfarcken, 1993;Doble, 1999;Hertz et al, 1999;Obrenovitch et al, 2000;Atlante et al, 2001;Pitt et al, 2003) neurodegenerative conditions. Excitotoxicity results from over-exposure of neurons to high concentrations of glutamate as a result of increased synthesis activity, decreased levels of catabolism, decreased transporter activity, and delayed re-uptake from the synaptic cleft after its release into the synapse.…”

Disruptions in the Regulation of Extracellular Glutamate by Neurons and Glia in the Rat Striatum Two Days after Diffuse Brain Injury

“…The discrepancy that MEAs detect neuronally derived glutamate, whereas microdialysis samples extracellular glutamate derived from non-neuronal origins, may be because of the inherent differences in the methodologies. The extensive damage to the local brain area during implantation of the microdialysis probe and the large area of tissue sampled (1-4 mm in length), restricts microdialysis measurements of glutamate to large regions far beyond synapses (Borland et al, 2005;Hillered et al, 2005;Jaquins-Gerstl and Michael, 2009;Obrenovitch, 1999, Obrenovitch et al, 2000Timmerman and Westerink 1997). Furthermore, the inadequate temporal resolution of microdialysis (*1-20 min) prevents microdialysis from detecting the rapid dynamic changes in extracellular glutamate that occur in the order of milliseconds to seconds (Diamond, 2005).…”