title: Long-term depression of neuron to glial signalling in rat cerebellar cortex.
abstract: Bergmann glial cells enclose synapses throughout the molecular layer of the cerebellum and express extrasynaptic AMPA receptors and glutamate transporters. Accordingly, stimulation of parallel fibres leads to the generation of inward currents in the glia due to AMPA receptor activation and electrogenic uptake of glutamate. Elimination of AMPA receptor Ca(2+) permeability leads to the withdrawal of glial processes and synaptic dysfunction, suggesting that AMPA receptor-mediated Ca(2+) signalling is essential for glial support of the neuronal network. Here we show that glial extrasynaptic currents (ESCs) exhibit activity-dependent plasticity, specifically, long-term depression during repetitive stimulation of parallel fibres at low frequencies (0.033-1 Hz) -- conditions in which Purkinje neuron excitatory postsynaptic currents (EPSCs) remain stable. Both the rate of onset and the magnitude of ESC depression increased with stimulation frequency. Depression was reversible following brief periods of stimulation, but became increasingly persistent as the duration of repetitive stimulation increased. All glial currents -- AMPA receptors, glutamate transporter and a recently discovered slow 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide (NBQX)-sensitive current -- were depressed. Increasing presynaptic release probability by doubling external Ca(2+) concentration did not affect the time course of depression, suggesting that neither decreased release probability nor fatigue of release sites contribute to depression. Inhibition of glutamate uptake caused a dramatic enhancement of the rate of depression, implicating glutamate in the underlying mechanism. The strength of neuron to glial signalling in the cerebellum is therefore dynamically regulated, independently of adjacent synapses, by the frequency of parallel fibre activity.
authors.affiliation: National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. tom.bellamy@bbsrc.ac.uk
authors.forename: Tomas C
authors.initials: TC
authors.lastname: Bellamy
authors.forename: David
authors.initials: D
authors.lastname: Ogden
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002525:Cerebellar Cortex / Q000166:cytology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013619:Tacrine / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D013619:Tacrine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D002118:Calcium