title: Absence of cerebellar long-term depression in mice lacking neuronal nitric oxide synthase.
abstract: Extensive pharmacological evidence suggests that nitric oxide (NO) is a crucial transmitter for cerebellar long-term depression (LTD), a long-lasting decrease in efficacy of the synapses from parallel fibers onto Purkinje neurons, triggered by coincident presynaptic activity and postsynaptic depolarization. We now show that LTD cannot be induced in Purkinje neurons under whole-cell patch clamp in cerebellar slices from young adult mice genetically lacking neuronal nitric oxide synthase (nNOS). This genetic evidence confirms the essentiality of NO and nNOS for LTD in young adult rodents. Surprisingly, LTD in cells from nNOS knockout mice cannot be rescued by photolytic uncaging of NO and cGMP inside Purkinje neurons, although such stimuli circumvent acute pharmacological inhibition of nNOS and soluble guanylate cyclase in normal rodents. Also slices from knockout mice show no deficit in cGMP elevation in response to exogenous NO. Therefore, prolonged absence of nNOS allows atrophy of the signaling pathway downstream of cGMP.
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla 92093-0647, USA.
authors.forename: V
authors.initials: V
authors.lastname: Lev-Ram
authors.forename: Z
authors.initials: Z
authors.lastname: Nebyelul
authors.forename: M H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: P L
authors.initials: PL
authors.lastname: Huang
authors.forename: R Y
authors.initials: RY
authors.lastname: Tsien
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D009412:Nerve Fibers / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D018408:Patch-Clamp Techniques; D010782:Photolysis; D011689:Purkinje Cells / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium