Rett Syndrome Microglia Damage Dendrites and Synapses by the Elevated Release of Glutamate

Maezawa et al. reported that a possible therapeutic target for Rett syndrome is microglia glutamate synthesis or release, confirm that NMDA glutamate receptor antagonist may improve autism spectrum disorders (ASD) (Niederhofer 2007), and suggest that glutaminase inhibitors or gap junction hemichannel blockers may be appropriate therapeutic targets.

Another potential therapeutic target is peroxynitrite. Agonists of NMDA receptors increase concentration of calcium leads to nitric oxide (NO) synthesis. NO reacts with free radical superoxide and produces the powerful oxidant peroxynitrite. Nitric oxide and peroxynitrite may cause glutamate release and neuronal death (Brown and Neher), and peroxynitrite is toxic for mitochondrial activity and DNA (Spencer, Wong et al. 1996). The hyperglutaminergic condition in ASD, the role of glutamate in production of inflammation (which is elevated in ASD; Blaylock and Strunecka, 2009), and peroxynitrite, toxicity of peroxynitrite for DNA, and the prevention of neuronal loss by scavengers of peroxynitrite in co-cultured neurons (Mander and Brown 2005) all point to peroxynitrite as a novel potential treatment target for autism.

Peroxynitrite decomposition catalysts block nitration of glutamate transporters, especially GLT1 and glutamine synthetase (Chen, Muscoli et al.). These two proteins have key roles in transmission of glutamate into the intracellular space. Inhibition of GLT1 and glutamine synthetase by peroxynitrite increases glutamate level and causes neurotoxicity. Therefore, therapeutic approaches intelligently targeting peroxynitrite in brain could be worthwhile to be further studied in preclinical experimental trials for management of ASD. Of course, it is a simplification of the association of peroxynitrite and glutamate with the proposed intervention here. Peroxynitrite has roles in other tissues that should be considered before jumping to this conclusion.

References

Blaylock, R. L. and A. Strunecka (2009). "Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders." Curr Med Chem 16(2): 157-70.

Brown, G. C. and J. J. Neher (2010). "Inflammatory Neurodegeneration and Mechanisms of Microglial Killing of Neurons." Mol Neurobiol. Mar 2. [Epub ahead of print].

Chen, Z., C. Muscoli, et al. (2010). "NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing." Pain 149(1):100-6.

Maezawa, I. and L. W. Jin (2010) "Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate." J Neurosci 30(15): 5346- 56.

Mander, P. and G. C. Brown (2005). "Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration." J Neuroinflammation 2: 20.

Niederhofer, H. (2007). "Glutamate antagonists seem to be slightly effective in psychopharmacologic treatment of autism." J Clin Psychopharmacol 27(3): 317-8.

Spencer, J. P., J. Wong, et al. (1996). "Base modification and strand breakage in isolated calf thymus DNA and in DNA from human skin epidermal keratinocytes exposed to peroxynitrite or 3-morpholinosydnonimine." Chem Res Toxicol 9(7): 1152-8.