The Cerebellar Dopaminergic System.

Paolo Flace,Giuseppe Anastasi,Salvatore Bertino,Gianfranco Gennarini,Paolo Livrea,Gianpaolo Antonio Basile,Diana Galletta,Massimo Gulisano,Simona Bianconi,Jacopo Junio Valerio Branca,Alessia Bramanti,Antonella Bizzoca

doi:10.3389/fnsys.2021.650614

Abstract

In the central nervous system (CNS), dopamine (DA) is involved in motor and cognitive functions. Although the cerebellum is not been considered an elective dopaminergic region, studies attributed to it a critical role in dopamine deficit-related neurological and psychiatric disorders [e.g., Parkinson's disease (PD) and schizophrenia (SCZ)]. Data on the cerebellar dopaminergic neuronal system are still lacking. Nevertheless, biochemical studies detected in the mammalians cerebellum high dopamine levels, while chemical neuroanatomy studies revealed the presence of midbrain dopaminergic afferents to the cerebellum as well as wide distribution of the dopaminergic receptor subtypes (DRD1-DRD5). The present review summarizes the data on the cerebellar dopaminergic system including its involvement in associative and projective circuits. Furthermore, this study also briefly discusses the role of the cerebellar dopaminergic system in some neurologic and psychiatric disorders and suggests its potential involvement as a target in pharmacologic and non-pharmacologic treatments.

Highlights

We found a low density of tyrosine hydroxylase (TH) immunoreactive fibers to be distributed in the lobules of the vermis and of both cerebellar hemispheres, whereas the dopamine transporter (DAT) immunoreactive fibers were only observed in the vermis of the following lobules II, III, IV, VIIIA, VIIIB, IX, and X (Table 1; Melchitzky and Lewis, 2000)
The present review extensively evidenced the available morphological, chemical, and functional data on the existence of a cerebellar dopaminergic system in mammals including humans, which consist of extrinsic fibers which originate mainly from the midbrain cerebellar dopaminergic nuclei (A8-A10; Ikai et al, 1992; Nelson et al, 1997) and of intrinsic dopaminergic neuronal subpopulations mainly composed of cortico-cerebellar projective neuron types, such as the Purkinje neuron and the synarmotic neuron, and by different cerebello-nuclear neuron types (Nelson et al, 1997; Delis et al, 2008; Flace, 2017; Flace et al, 2018a, 2019b)
This review evidenced the presence of direct dentate-SNpc and dentate-ventral tegmental area (VTA) interconnections (Milardi et al, 2016; Flace et al, 2017, 2018a, 2019b, 2020), which may play a relevant modulatory role in DA release at the prefrontal cortex (PFC) (Mittleman et al, 2008; Rogers et al, 2013) and highlight the possible involvement of dopaminergic cerebellar circuits in dopaminergic related disorders such as Parkinson’s disease (PD) (Wu and Hallett, 2013; Flace et al, 2018a, 2019b, 2020), SCZ (Martin and Albers, 1995; Mittleman et al, 2008; Rogers et al, 2013; Parker et al, 2014), and autism spectrum disorders (ASD) (Kemper and Bauman, 1993; Mittleman et al, 2008; Rogers et al, 2013)

Summary

Introduction

The neurotransmitter systems traditionally involved in the synaptic and extrasynaptic interactions may include the excitatory glutamatergic system (Clements et al, 1987; Batini et al, 1992; Ottersen, 1993; Zhang and Ottersen, 1993; Batchelor et al, 1994; Grandes et al, 1994; Nusser and Somogyi, 1997; Knöpfel and Grandes, 2002; Hioki et al, 2003; SanchezPerez et al, 2005; Benagiano et al, 2011; Mugnaini et al, 2011; Uusisaari and De Schutter, 2011; Mapelli et al, 2015) as well as the inhibitory GABAergic and glycinergic systems (Gabbott et al, 1986; Wuenschell et al, 1986; Batini et al, 1992; Ottersen, 1993; Wisden et al, 1996; Sastry et al, 1997; Benagiano et al, 2000a,b; Flace et al, 2004; Crook et al, 2006; Tabata and Kano, 2006; Uusisaari and De Schutter, 2011; Mapelli et al, 2015), which are both involved in intrinsic and projective cerebellar circuits (Fredette and Mugnaini, 1991; Uusisaari and De Schutter, 2011; Ankri et al, 2015; Mapelli et al, 2015; Gao et al, 2016). Data on the presence and distribution of monoaminergic systems in the mammalian cerebellum are still incomplete and not fully analyzed. In studies using histofluorescence (Hökfelt and Fuxe, 1969) or immunohistochemical methods through specific 5-HT antiserum, in several mammals, including humans, the presence of a cerebellar serotonergic fiber system (Takeuchi et al, 1982; Kerr and Bishop, 1991; Ottersen, 1993; Kitzman and Bishop, 1997; Flace, 2017, 2019a), composed by 5-HT immunoreactive axonal plexuses of fibers and by neuronal cell bodies and processes distributed in the cerebellar cortical layers and in the deep cerebellar nuclei, has been demonstrated (Takeuchi et al, 1982; Bishop and Ho, 1985; Kerr and Bishop, 1991; Crivellato et al, 1992; Flace, 2017, 2019a)

Objectives

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Conclusion