Astrocytes Adjust AMPA Receptors to Protect Neurons

Behind every successful neuron, and some unsuccessful ones, there are astrocytes. These accessory cells nurture and protect their finicky neighbors by providing nutrients, neurotrophic factors, and physical support for neurons. However, they can also sow the seeds of neurodegeneration, as they do in one type of amyotrophic lateral sclerosis. In that disease, astrocytes that express a pathogenic mutant of superoxide dismutase 1 (SOD1) protein cause motor neuron death (see ARF related news story).

New work from Ludo Van Den Bosch, Wim Robberecht, and colleagues at the University of Leuven, Belgium, sheds light on how astrocytes make life-or-death decisions for motor neurons. In a paper published in the online edition of PNAS, they report that astrocytes regulate neuronal sensitivity to excitotoxicity by altering the makeup of AMPA-type glutamate receptors on the neurons. Astrocytes that express mutant SOD1 lose their ability to regulate AMPA receptor properties and to protect neurons.

Excitotoxicity is important in the pathology of ALS, stroke, and epilepsy, and is attracting attention in Alzheimer disease, too (see ARF related news story). Neurons are thought to die from excitotoxicity after an influx of excess calcium through AMPA receptors. The susceptibility of neurons depends on the calcium permeability of these receptors, which is itself regulated by expression of the GluR2 subunit. Receptors containing GluR2 are relatively impermeable to calcium and protect against excitotoxicity; those lacking GluR2 are more permeable and render cells at higher risk for death.

Since low GluR2 expression contributes to cell death in several diseases, the investigators wanted to understand how the levels of the subunit are regulated. To do this, first authors Philip Van Damme and Elke Bogaert compared neurons from two rat strains, Wistar and Holtzman, which had similar numbers of AMPA receptors, but different sensitivity to AMPA-mediated excitotoxicity. Ventral spinal cord motor neurons from Wistar rats were more sensitive, both in vitro and in vivo, to excitotoxic insults. The difference was due to a reduction in the relative levels of GluR2 mRNA and protein in the Wistar rats compared to the Holtzman strain.

When the investigators cultured Wistar motor neurons on astrocytes derived from Holtzman rats and vice versa, they discovered that astrocytes control the levels of neuronal GluR2. The Holtzman astrocytes drove higher expression of GluR2 in Wistar motor neurons, and the neurons acquired greater resistance to excitotoxicity. Conversely, Wistar astrocytes supported lower GluR2 expression in Holtzman neurons, with an increase in sensitivity to AMPA stimulation. The effects were specific to astrocytes from the ventral part of the spinal cord, and not from the dorsal region or the cerebellum or cortex.

The death of motor neurons in ALS has been linked to mutant SOD1 expression in astrocytes, and so the authors tested the effects of mutant-expressing astrocytes in their neuronal cultures. Holtzman astrocytes containing mutant SOD1 lost their capacity to increase GluR2 expression on neurons, or to protect neurons from excitotoxicity. The investigators observed the same effect in vivo: expression of mutant SOD1 in transgenic Holtzman rats abolished the relatively higher levels of GluR2 expression seen in wild-type Holtzman rats. This result suggests that SOD1-transgenic Holtzman rats would gain no extra protection against ALS-like pathology compared to SOD1-transgenic Wistars, and indeed the authors observed that the SOD1 transgenic animals, whether Holtzman or Wistar, had a similar extent of motor neuron loss and reduction in life span.

It's known that astrocytes can buffer excitotoxicity via their ability to take up excess glutamate. The current work suggests that by regulating neuronal GluR2 expression, they may possess yet another mechanism to protect neurons. While it is unclear how astrocytes signal to neurons to modulate GluR2 expression, the investigators did show that either conditioned media or membrane preparations from Holtzman astrocytes could increase GluR2 expression, and that the activity was destroyed by proteolysis. Equally mysterious is how mutant SOD1 might affect the astrocyte-neuron interaction.—Pat McCaffrey

Comments

  1. Astrocytes are three times more abundant in brain than are neurons. They control the synaptic boutons of the neurons by controlling the amount of receptor in there (see Perea and Araque, 2007). Now these researchers discovered that astrocytes can control the number of GluR2. Taken together, the research suggests that in brain, astrocytes probably are doing some of the work that the cell matrix performs in other parts of the body. Now we need to study how astrocytes are doing that.

    SOD1 is an enzyme involved in oxidative stress. I suspect that astrocytes are controlling the oxidative stress in brain to save neurons from oxidative damage. Also, astrocytes probably perform some immune functions in brain. We published that astrocytes control the number of IL-1 receptors and the number of LPS receptors (TLR4). So I agree with this paper looking for astrocyte functions. I personally think astrocytes are even more important cells than are neurons. Neurons communicate with other cells, but astrocytes are also crucial to memory.

    References:

    Blanco AM, Vallés SL, Pascual M, Guerri C. Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes. J Immunol. 2005 Nov 15;175(10):6893-9. PubMed.

    Vallés SL, Blanco AM, Pascual M, Guerri C. Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol. 2004 Oct;14(4):365-71. PubMed.

    Blanco AM, Pascual M, Valles SL, Guerri C. Ethanol-induced iNOS and COX-2 expression in cultured astrocytes via NF-kappa B. Neuroreport. 2004 Mar 22;15(4):681-5. PubMed.

    Pascual M, Valles SL, Renau-Piqueras J, Guerri C. Ceramide pathways modulate ethanol-induced cell death in astrocytes. J Neurochem. 2003 Dec;87(6):1535-45. PubMed.

    Vallés S, Pitarch J, Renau-Piqueras J, Guerri C. Ethanol exposure affects glial fibrillary acidic protein gene expression and transcription during rat brain development. J Neurochem. 1997 Dec;69(6):2484-93. PubMed.

    Vallés SL, Borrás C, Gambini J, Furriol J, Ortega A, Sastre J, Pallardó FV, Viña J. Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38. Aging Cell. 2008 Jan;7(1):112-8. Epub 2007 Nov 21 PubMed.

    View all comments by Soraya Valles

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References

News Citations

  1. Glia—Absolving Neurons of Motor Neuron Disease
  2. Do "Silent" Seizures Cause Network Dysfunction in AD?

Further Reading

Primary Papers

  1. Van Damme P, Bogaert E, Dewil M, Hersmus N, Kiraly D, Scheveneels W, Bockx I, Braeken D, Verpoorten N, Verhoeven K, Timmerman V, Herijgers P, Callewaert G, Carmeliet P, Van Den Bosch L, Robberecht W. Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14825-30. PubMed.

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