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The Journal of Neuroscience, March 8, 2006, 26(10):2673-2683; doi:10.1523/JNEUROSCI.4689-05.2006

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Cellular/Molecular
NMDA Receptors Mediate Neuron-to-Glia Signaling in Mouse Cortical Astrocytes

Ulyana Lalo,¹ Yuri Pankratov,¹ Frank Kirchhoff,^2,3 R. Alan North,¹ and Alexei Verkhratsky¹

¹Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom, ²Max Planck Institute of Experimental Medicine and ³Deutsche Forschungsgemeinschaft Research Center for Molecular Physiology of the Brain, D-37075 Goettingen, Germany

Correspondence should be addressed to Prof. Alexei Verkhratsky, Faculty of Life Sciences, The University of Manchester, 1.124 Stopford Building, Oxford Road, Manchester M13 9PT, UK. Email: alex.verkhratsky{at}manchester.ac.uk

Chemical transmission between neurons and glial cells is an important element of integration in the CNS. Here, we describe currents activated by NMDA in cortical astrocytes, identified in transgenic mice that express enhanced green fluorescent protein under control of the human glial fibrillary acidic protein promoter. Astrocytes were studied by whole-cell voltage clamp either in slices or after gentle nonenzymatic mechanical dissociation. Acutely isolated astrocytes showed a three-component response to glutamate. The initial rapid component was blocked by 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), which is an antagonist of AMPA receptors (IC₅₀, 2 µM), and the NMDA receptor antagonist D-AP-5 blocked the later sustained component (IC₅₀, 0.6 µM). The third component of glutamate application response was sensitive to D,L-threo--benzyloxyaspartate, a glutamate transporter blocker. Fast application of NMDA evoked concentration-dependent inward currents (EC₅₀, 0.3 µM); these showed use-dependent block by (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801). These NMDA-evoked currents were linearly dependent on membrane potential and were not affected by extracellular magnesium at concentrations up to 10 mM. Electrical stimulation of axons in layer IV–VI induced a complex inward current in astrocytes situated in the cortical layer II, part of which was sensitive to MK-801 at holding potential –80 mV and was not affected by the AMPA glutamate receptor antagonist NBQX. The fast miniature spontaneous currents were observed in cortical astrocytes in slices as well. These currents exhibited both AMPA and NMDA receptor-mediated components. We conclude that cortical astrocytes express functional NMDA receptors that are devoid of Mg²⁺ block, and these receptors are involved in neuronal–glial signal transmission.

Key words: NMDA receptors; Mg²⁺ insensitivity; cortex; GFAP–GFP mice; astrocytes; neuronal–glial interactions

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Received June 1, 2005; revised Dec. 30, 2005; accepted Jan. 3, 2006.

Correspondence should be addressed to Prof. Alexei Verkhratsky, Faculty of Life Sciences, The University of Manchester, 1.124 Stopford Building, Oxford Road, Manchester M13 9PT, UK. Email: alex.verkhratsky{at}manchester.ac.uk

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