Abstract
Classically, the cerebellum has been thought to play a significant role in motor coordination. However, a growing body of evidence for novel neural connections between the cerebellum and various brain regions indicates that the cerebellum also contributes to other brain functions implicated in reward, language, and social behavior. Cerebellar Purkinje cells (PCs) make inhibitory GABAergic synapses with their target neurons: other PCs and Lugaro/globular cells via PC axon collaterals, and neurons in the deep cerebellar nuclei (DCN) via PC primary axons. PC-Lugaro/globular cell connections form a cerebellar cortical microcircuit, which is driven by serotonin and noradrenaline. PCs’ primary outputs control not only firing but also synaptic plasticity of DCN neurons following the integration of excitatory and inhibitory inputs in the cerebellar cortex. Thus, strong PC-mediated inhibition is involved in cerebellar functions as a key regulator of cerebellar neural networks. In this review, we focus on physiological characteristics of GABAergic transmission from PCs. First, we introduce monoaminergic modulation of GABAergic transmission at synapses of PC-Lugaro/globular cell as well as PC-large glutamatergic DCN neuron, and a Lugaro/globular cell-incorporated microcircuit. Second, we review the physiological roles of perineuronal nets (PNNs), which are organized components of the extracellular matrix and enwrap the cell bodies and proximal processes, in GABA release from PCs to large glutamatergic DCN neurons and in cerebellar motor learning. Recent evidence suggests that alterations in PNN density in the DCN can regulate cerebellar functions.
Highlights
The characterization of the modulation of synaptic transmission and intrinsic neuronal excitation is significant for a precise comprehension of cerebellar motor learning and cognitive processing depending on the cerebellum
Purkinje cells (PCs) project their primary axons to the deep cerebellar nuclei (DCN) and collaterals within the cerebellar cortex, especially around the PC layer to form negative feedback connections. Both the GABAergic transmission from PCs is important because the primary axons transmit signals, which are formed by PCs after integrating excitatory and inhibitory input signals, and the axon collaterals form Lugaro/globular cell-incorporated microcircuits
5-HT released in the cerebellar cortex activates the Lugaro/globular cell-incorporated microcircuit, facilitating and synchronizing the activity of PC clusters, followed by a return to the basal activity of Lugaro/globular cells. 5-HT-evoked excitatory effects on large glutamatergic DCN neurons could be independent of the 5-HT-mediated activation of the microcircuit in the cerebellar cortex, because serotonergic fibers from various brainstem nuclei innervate separately into the cerebellar cortex and DCN (Kitzman and Bishop, 1994)
Summary
The cerebellum is well known to play a crucial role in fine movement and motor activity (Ito, 1984), recent evidence suggest that the cerebellum is increasingly implicated in a variety of brain functions, including reward prediction (Wagner et al, 2017; Heffley et al, 2018; Carta et al, 2019; Kostadinov et al, 2019), motor planning (Gao et al, 2018; Chabrol et al, 2019; Wagner et al, 2019), and higher cognitive functions such as language and social behavior (Fiez and Petersen, 1998; Van Overwall et al, 2014; Schmahmann et al, 2019). A recent morphological study proposed that Lugaro cells can disinhibit cerebellar cortical activities following administration of 5-HT (Dieudonné and Dumoulin, 2000; Dumoulin et al, 2001; Dean et al, 2003; Hirono et al, 2012) This evidence suggests that these cells are the main targets of 5-HT released from serotonergic beaded afferent fibers in the cerebellar cortex. Lugaro/globular cells exhibit inhibitory synaptic currents at higher frequencies compared to Golgi cells (Dieudonné, 2001; Hirono et al, 2012, 2017), since their somata and proximal dendrites are enwrapped by calbindin-positive boutons, meaning they are synaptic inputs from PCs (Palay and Chan-Palay, 1974; Lainé and Axelrad, 2002; Crook et al, 2007; Simat et al, 2007). Globular, but not Lugaro cells, are excited to elicit firing during administration of NA (Hirono et al, 2012), suggesting that globular cells could express α1and/or β2-adrenoceptors similar to molecular layer interneurons
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