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The Journal of Neuroscience, December 15, 2001, 21(24):9877-9887

Role of Calcium, Glutamate Neurotransmission, and Nitric Oxide in Spreading Acidification and Depression in the Cerebellar Cortex

Gang Chen, Robert L. Dunbar, Wangcai Gao, and Timothy J. Ebner

Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455

This study investigated the mechanisms underlying the recently reported fast spreading acidification and transient depression in the cerebellar cortex in vivo. Spreading acidification was evoked by surface stimulation in the rat and mouse cerebellar cortex stained with the pH-sensitive dye neutral red and monitored using epifluorescent imaging. The probability of evoking spreading acidification was dependent on stimulation parameters; greater frequency and/or greater amplitude were more effective. Although activation of the parallel fibers defined the geometry of the spread, their activation alone was not sufficient, because blocking synaptic transmission with low Ca²⁺ prevented spreading acidification. Increased postsynaptic excitability was also a major factor. Application of either AMPA or metabotropic glutamate receptor antagonists reduced the likelihood of evoking spreading acidification, but stronger stimulation intensities were still effective. Conversely, superfusion with GABA receptor antagonists decreased the threshold for evoking spreading acidification. Blocking nitric oxide synthase (NOS) increased the threshold for spreading acidification, and nitric oxide donors lowered the threshold. However, spreading acidification could be evoked in neuronal NOS-deficient mice (B6;129S-Nos1^tm1plh). The depression in cortical excitability that accompanies spreading acidification occurred in the presence of AMPA and metabotropic glutamate receptor antagonists and NOS inhibitors. These findings suggest that spreading acidification is dependent on extracellular Ca²⁺ and glutamate neurotransmission with a contribution from both AMPA and metabotropic glutamate receptors and is modulated by nitric oxide. Therefore, spreading acidification involves both presynaptic and postsynaptic mechanisms. We hypothesize that a regenerative process, i.e., a nonpassive process, is operative that uses the cortical architecture to account for the high speed of propagation.

Key words: cerebellum; calcium; glutamate; nitric oxide; optical imaging; neutral red; rat; transgenic mouse; spreading depression; calcium waves

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21249877-11$05.00/0

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