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An NMDA Receptor/Nitric Oxide Cascade Is Involved in Cerebellar LTD But Is Not Localized to the Parallel Fiber Terminal

Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 24 June 2005; accepted in final form 17 August 2005

Long-term depression (LTD) of the parallel fiber-Purkinje cell synapse in the cerebellum is a cellular model system that has been suggested to underlie certain forms of motor learning. Induction of cerebellar LTD requires a postsynaptic kinase limb involving activation of mGluR1, protein kinase C (PKC), and phosphorylation of ser-880 on the AMPA receptor subunit GluR2. Several lines of evidence have also implicated a complementary phosphatase limb in which N-methyl-D-aspartate (NMDA) receptor-mediated Ca²⁺ influx activates neuronal nitric oxide synthase (nNOS), the ultimate consequences of which are mediated by nitric oxide (NO), cGMP, and inhibition of postsynaptic protein phosphatases. However, the cellular localization of an NMDA/NO cascade has been complicated by the fact that neither functional NMDA receptors nor nNOS are expressed in Purkinje cells. This has lead to a proposal in which NMDA receptors activate nNOS in parallel fibers. Here, we confirm that pharmacological blockade of NMDA receptor or NO signaling blocks induction of LTD. However, no evidence was found for functional NMDA receptors in parallel fiber terminals: blockade of NMDA receptors did not alter either presynaptic Ca²⁺ transients or the frequency of miniature excitatory postsynaptic currents. NMDA receptor blockade did abolish a slow depolarization evoked by burst stimulation of parallel fiber-stellate cell synapses. The application of NMDA evoked a Ca²⁺ transient in stellate cell terminals but not in parallel fiber terminals. These results are consistent with the hypothesis that an NMDA receptor/NO cascade involved in cerebellar LTD is localized to interneurons rather than parallel fibers.

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