Abstract
Inhibitory synapses can be organized in different ways and be regulated by a multitude of mechanisms. One of the best known examples is provided by the inhibitory synapses formed by Golgi cells onto granule cells in the cerebellar glomeruli. These synapses are GABAergic and inhibit granule cells through two main mechanisms, phasic and tonic. The former is based on vesicular neurotransmitter release, the latter on the establishment of tonic γ-aminobutyric acid (GABA) levels determined by spillover and regulation of GABA uptake. The mechanisms of post-synaptic integration have been clarified to a considerable extent and have been shown to differentially involve α1 and α6 subunit-containing GABA-A receptors. Here, after reviewing the basic mechanisms of GABAergic transmission in the cerebellar glomeruli, we examine how inhibition controls signal transfer at the mossy fiber-granule cell relay. First of all, we consider how vesicular release impacts on signal timing and how tonic GABA levels control neurotransmission gain. Then, we analyze the integration of these inhibitory mechanisms within the granular layer network. Interestingly, it turns out that glomerular inhibition is just one element in a large integrated signaling system controlled at various levels by metabotropic receptors. GABA-B receptor activation by ambient GABA regulates glutamate release from mossy fibers through a pre-synaptic cross-talk mechanisms, GABA release through pre-synaptic auto-receptors, and granule cell input resistance through post-synaptic receptor activation and inhibition of a K inward-rectifier current. Metabotropic glutamate receptors (mGluRs) control GABA release from Golgi cell terminals and Golgi cell input resistance and autorhythmic firing. This complex set of mechanisms implements both homeostatic and winner-take-all processes, providing the basis for fine-tuning inhibitory neurotransmission and for optimizing signal transfer through the cerebellar cortex.
Highlights
The fundamental anatomical and functional organization of the cerebellar cortex was defined since the ‘60s, thanks to improvements in anatomical and physiological techniques applied to the brain tissue (Eccles, 1967; Palay and Chan-Palay, 1974)
Granule cell excitation and inhibition were shown to occur inside the glomeruli, where each granule cell is contacted by mossy fiber terminals and in turn receives synapses from Golgi cells (Figure 1) (Hámori and Somogyi, 1983; Jakab and Hámori, 1988)
While phasic inhibition was observed quite early to generate typical inhibitory post-synaptic currents (IPSCs) (Puia et al, 1994; Kaneda et al, 1995; Wall and Usowicz, 1997; Rossi and Hamann, 1998) and potentials (IPSPs) (Armano et al, 2000), growing interest has recently been raised by a tonic form of inhibition, mediated by high-affinity extrasynaptic GABA-A receptors activated by low ambient GABA concentrations in the extracellular space of the glomerulus
Summary
Integration and regulation of glomerular inhibition in the cerebellar granular layer circuit. One of the best known examples is provided by the inhibitory synapses formed by Golgi cells onto granule cells in the cerebellar glomeruli These synapses are GABAergic and inhibit granule cells through two main mechanisms, phasic and tonic. After reviewing the basic mechanisms of GABAergic transmission in the cerebellar glomeruli, we examine how inhibition controls signal transfer at the mossy fiber-granule cell relay. Metabotropic glutamate receptors (mGluRs) control GABA release from Golgi cell terminals and Golgi cell input resistance and autorhythmic firing. This complex set of mechanisms implements both homeostatic and winner-take-all processes, providing the basis for fine-tuning inhibitory neurotransmission and for optimizing signal transfer through the cerebellar cortex
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