Somatodendritic release of glutamate regulates synaptic inhibition in cerebellar Purkinje cells via autocrine mGluR1 activation.
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.
Duguid
Ian C
IC
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom.
Pankratov
Yuriy
Y
Moss
Guy W J
GW
Smart
Trevor G
TG
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
D063385:Cannabinoid Receptor Modulators; D018094:Receptors, Metabotropic Glutamate; D050600:SNARE Proteins; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid