Cerebellar Golgi cell inhibition gets slowly more complicated

Abstract

The cellular architecture of the cerebellum that was so beautifully described by Ramon y Cajal (1899) offers one of the most complete systems for understanding how networks of excitatory and inhibitory neurons interact with one another to control the flow of sensory information in the mammalian brain. However, despite decades of anatomical and electrophysiological studies, this relatively simple and well-defined neuronal circuit still holds a few surprises. For example, in a recent issue of The Journal of Physiology, Holtzman and colleagues (2011) demonstrate some unusual features of cerebellar Golgi cell function. Our view of cerebellar Golgi cells has, in many respects, changed very little since Eccles first described the basic features of feed-forward and feed-back inhibition of granule cells by Golgi cell interneurons in the 1960s (Eccles, 1964). Cerebellar Golgi cells are one of the few cell types that can control granule cell firing within the cerebellar cortex due to their ability to release the inhibitory neurotransmitter γ-aminobutyric acid (GABA) onto both synaptic and extrasynaptic GABAA receptors that are expressed on granule cells (Brickley et al. 1996; Crowley et al. 2009). The current study is concerned with the excitatory drive onto Golgi cells that triggers the release of this GABA onto granule cells. Excitatory drive onto Golgi cells arises from glutamatergic mossy fibre inputs that convey sensory information into the cerebellar cortex (Kanichay & Silver, 2008), and from the glutamate released from granule cell axons that form the parallel fibre inputs onto Golgi cell dendrites (Dieudonne, 1998). It is this feedback loop involving the mossy-fibre → granule cell → Golgi cell → granule cell circuit that has been the focus of attention for the current study. Holtzmann et al. used in vivo recording techniques to monitor action potential firing patterns from Golgi cells during parallel fibre stimulation. In this way they confirmed an observation that was first made in an acute in vitro slice preparation of the cerebellum (Watanbe & Nakanishi, 2003) that the release of glutamate from granule cells leads to a decrease in Golgi cell firing through activation of mGluR2 receptors. This contradicts the classical view that granule cells serve only to excite Golgi cells. The decrease in Golgi firing that occurs following parallel fibre input lasts for hundreds of milliseconds, resulting in a conspicuous disinhibition of granule cells. This sustained depression of Golgi cell firing has been reported previously in vivo (Vos et al. 1999; Holtzman et al. 2006), but the authors have now confirmed the involvement of mGluR2 activation in this process. Moreover, the authors now show that it is possible to trigger this mGluR2-mediated disinhibition by modulating granule cell excitability through an enhancement of the tonic inhibition that is present on granule cells. In this study, tonic inhibition of granule cells was enhanced using the application of the GABA agonist gaboxadol (or THIP) that is known to have a selective action on extrasynaptic GABAA receptors that contain the delta subunit when used at sub-micromolar concentrations. Obviously, in an in vivo study of this type it is difficult to establish the effective concentration of the drug within the cerebellum, but it would appear that increased glutamate release from granule cells can lead to mGluR2 activation and, therefore, inhibition of Golgi cell firing. The authors further speculate that a spillover-type mechanism is involved in this glutamate activation of mGluR receptors on Golgi cells in an analogous manner to the GABA activation of extrasynaptic GABAA receptors. Spillover refers to the fact that glutamate diffuses out of the synaptic cleft to activate mGluR2 receptors located some distance away from the synapse. Binding of this ‘escaped’ glutamate to mGluR2 receptors is assumed to reduce Golgi cell firing due to an increased potassium permeability associated with activation of this G-protein-coupled receptor. However, an involvement of other mechanisms such as electrical coupling via gap-junctions cannot be ruled out at this stage (e.g. Vervaeke et al. 2010). Nevertheless, it is interesting to speculate that this form of slow intercellular signalling may support oscillations in granule cell firing such that modulation of granule cell activity levels over such slow time-scales are matched to incoming sensory inputs of the type observed during sleep and certain types of behaviour (Dugueet al. 2009; Roset al. 2009). Given the importance of the cerebellar cortex in the acquisition of new motor skills, an important challenge for the future will be to determine how these types of intercellular signalling mechanisms may impact upon granule cell firing during motor learning tasks.