Download Evidence that granule cells can mediate inhibition of Golgi cells via

Session CEREBELLUM
Evidence that granule cells can mediate inhibition of Golgi
cells via mGluR2 receptors in vivo
Tahl Holtzman, Tian X. Zhao & Steve A. Edgley
Department of Physiology, Development and Neuroscience, Downing Street, Cambridge, UK
th247 @cam.ac.uk
Golgi cells are a critical element of the cerebellar cortical circuitry. The anatomical arrangement of
their connections has inspired the view that Golgi cells provide negative feedback over granule
cells, limiting their activity and perhaps filtering of mossy fibre inputs. In this light, Golgi cells are
of pivotal importance in normal cerebellar function as they directly influence granule cells, the main
excitatory input to Purkinje cells. Recent work in our laboratory has revealed an unexpected
response pattern in Golgi cells: somatosensory stimulation depresses the continuous firing of Golgi
cells, often for several hundred milliseconds, and leads to concomitant increases in Purkinje cell
activity. Since Golgi cells produce phasic inhibition (action potential dependent) and tonic
inhibition (synaptic spillover) in granule cells such long lasting depression responses are likely to
substantially disinhibit granule cells, leading in turn to an increase in their activity.
In vitro, activation of mGluR2 receptors has been recently reported to hyperpolarise Golgi cells for
approximately 300 ms, via coupling to GIRK outward K+ channels, activated by glutamate released
from parallel fibres (Watanabe and Nakanishi, 2003). The time-course of these hyperpolaristions
make them an ideal candidate for mediating the long lasting depression responses evoked by
stimulation of peripheral afferents in Golgi cells in vivo (Holtzman et al., 2006). Using urethane
anaesthetised rats (1g / Kg) we combined extracellular recording of the evoked responses of Golgi
cells with local iontophoresis of potent mGluR2 receptor antagonists (LY341495 or APICA). The
Golgi cell responses were robustly attenuated by either of the mGluR2 antagonists, providing
evidence that mGluR2 driven hyperpolarisation contributes a substantial component of the
responses.
In conclusion, these results show that glutamate released from granule cells is likely to inhibit Golgi
cell firing, thereby reinforcing further granule cell activity through positive feedback. In this sense,
granule cells are acting as feed-forward inhibitors of Golgi cells, the net result being an
enhancement of mossy fibre to granule cell transmission. This challenges our current understanding
of the interaction between Golgi cells and granule cells and the contribution they make to cerebellar
information processing.
Holtzman T, Rajapaksa T, Mostofi A, Edgley SA (2006) Different responses of rat cerebellar
Purkinje cells and Golgi cells evoked by widespread convergent sensory inputs. J Physiol
574:491-507.
Watanabe D, Nakanishi S (2003) mGluR2 postsynaptically senses granule cell inputs at Golgi cell
synapses. Neuron 39:821-829.