title: Somatodendritic release of glutamate regulates synaptic inhibition in cerebellar Purkinje cells via autocrine mGluR1 activation.
abstract: In the cerebellum, the process of retrograde signaling via presynaptic receptors is important for the induction of short- and long-term changes in inhibitory synaptic transmission at interneuron-Purkinje cell (PC) synapses. Endocannabinoids, by activating presynaptic CB1 receptors, mediate a short-term decrease in inhibitory synaptic efficacy, whereas glutamate, acting on presynaptic NMDA receptors, induces a longer-latency sustained increase in GABA release. We now demonstrate that either low-frequency climbing fiber stimulation or direct somatic depolarization of Purkinje cells results in SNARE-dependent vesicular release of glutamate from the soma and dendrites of PCs. The activity-dependent release of glutamate caused the activation of postsynaptic metabotropic glutamate receptor 1 (mGluR1) on PC somatodendritic membranes, resulting in the cooperative release of endocannabinoids and an mGluR1-mediated slow membrane conductance. The activity of excitatory amino acid transporters regulated the spatial spread of glutamate and thus the extent of PC mGluR1 activation. We propose that activity-dependent somatodendritic glutamate release and autocrine activation of mGluR1 on PCs provides a powerful homeostatic mechanism to dynamically regulate inhibitory synaptic transmission in the cerebellar cortex.
authors.affiliation: Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Duguid
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Pankratov
authors.forename: Guy W J
authors.initials: GW
authors.lastname: Moss
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
mesh_terms: D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D004558:Electric Stimulation; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D050600:SNARE Proteins / Q000378:metabolism; D013570:Synaptic Membranes / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D063385:Cannabinoid Receptor Modulators; D018094:Receptors, Metabotropic Glutamate; D050600:SNARE Proteins; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid