Abstract
Neuronal inhibition can be defined as a spatiotemporal restriction or suppression of local microcircuit activity. The importance of inhibition relies in its fundamental role in shaping signal processing in single neurons and neuronal circuits. In this context, the activity of inhibitory interneurons proved the key to endow networks with complex computational and dynamic properties. In the last 50 years, the prevailing view on the functional role of cerebellar cortical inhibitory circuits was that excitatory and inhibitory inputs sum spatially and temporally in order to determine the motor output through Purkinje cells (PCs). Consequently, cerebellar inhibition has traditionally been conceived in terms of restricting or blocking excitation. This assumption has been challenged, in particular in the cerebellar cortex where all neurons except granule cells (and unipolar brush cells in specific lobules) are inhibitory and fire spontaneously at high rates. Recently, a combination of electrophysiological recordings in vitro and in vivo, imaging, optogenetics and computational modeling, has revealed that inhibitory interneurons play a much more complex role in regulating cerebellar microcircuit functions: inhibition shapes neuronal response dynamics in the whole circuit and eventually regulate the PC output. This review elaborates current knowledge on cerebellar inhibitory interneurons [Golgi cells, Lugaro cells (LCs), basket cells (BCs) and stellate cells (SCs)], starting from their ontogenesis and moving up to their morphological, physiological and plastic properties, and integrates this knowledge with that on the more renown granule cells and PCs. We will focus on the circuit loops in which these interneurons are involved and on the way they generate feed-forward, feedback and lateral inhibition along with complex spatio-temporal response dynamics. In this perspective, inhibitory interneurons emerge as the real controllers of cerebellar functioning.
Highlights
Reviewed by: Christian Hansel, University of Chicago, United States Marylka Yoe Uusisaari, Okinawa Institute of Science and Technology Graduate University, Japan
Cajal (1854–1934), by applying Golgi staining to the cerebellum, confirmed the cell types that Golgi had identified and added a detailed morphological characterization of all the elements of the cerebellar cortex, including stellate cells (SCs) and basket cells (BCs) as we know them today (Cajal, 1888). His great contribution was not properly exploited until the 1960s when Rodolfo Llinas characterized and defined the excitatory and inhibitory nature of all synaptic interactions within the cerebellar cortex (Eccles et al, 1966a). He demonstrated that all connectivities in the cerebellar cortex were inhibitory with the exception of the mossy fiber (MF)-granule cell-parallel fiber (PF) system and climbing fiber (CF) input (Eccles et al, 1966b) Llinas’s experiments showed that the stimulation of parallel fibers (PFs) excited molecular layer (ML) interneurons and evoked in Purkinje cells (PCs) an early excitatory postsynaptic potential (EPSP) followed by disynaptic and prolonged inhibitory postsynaptic potentials (IPSPs) that were strongly dendritic as well as somatic (Eccles, 1967)
The concept has emerged that neuron properties and network dynamics in the cerebellar inhibitory circuit are more complex than originally thought. Both in the granular and in the ML, cerebellar interneurons are involved in complex inhibitory chains generating feedback, feedforward and lateral inhibition that regulate spatio-temporal dynamics of fundamental importance to determine the processing capabilities of the cerebellar cortex
Summary
The cerebellar cortex consists of three layers, namely the molecular layer (ML), the Purkinje cell layer (PCL) and the granular layer (GL; Figure 1). The inhibitory control exerted by PCs on DCN neurons can be powerfully modulated by local inhibitory circuits formed by basket and stellate cells (SCs) These latter receive excitatory synapses from PFs and inhibitory synapses from PC axon collaterals (Crook et al., 2007; Witter et al, 2016). The LCs are located just beneath the PCL and are the primary target of serotonin released from extracerebellar fibers (Lainé and Axelrad, 1998) Their axons contact basket and SC soma and dendrites in the ML and, through collaterals, form a major input to Golgi cells (Dieudonné and Dumoulin, 2000). Current evidences indicate that these cells use GABA and glycine as transmitters (Flace et al, 2004; Tanaka and Ezure, 2004; Crook et al, 2006)
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