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Dopamine: the neglected mediator of cerebellum to unravel schizophrenia, ADHD, ASD and sisters

Although the presence of a dopaminergic system in the cerebellum is in part predictable, currently the cerebellum is not strictly considered a dopaminergic area.

In biochemical studies, high levels of dopamine (DA) in the human postmortem cerebellum and in the rat and monkey cerebellum has been detected. Furthermore, in the mammalian cerebellum, in vivo PET studies revealed a significant presence of selective dopamine transporter ligands. Chemical neuroanatomy studies on the detection of dopaminergic neuronal elements in the cerebellum of mammals (including human) makes use of direct antisera against DA and of radioactive dopaminergic ligands or antisera against the specific dopaminergic marker, the dopamine transporter (DAT), the indirect marker of the dopaminergic neurotransmission DARPP-32, a protein involved in dopaminergic neuronal synaptic signaling or, indirectly, by means of antisera against tyrosine hydroxylase (TH), which catalyzes the conversion of L-tyrosine to L-DOPA; and vesicular monoamine transporter 2 (VMAT2), the transporter of all known monoamine neurotransmitters.

In the human cerebellum, immunohistochemical experiments revealed the presence of DAT immunoreactive fibers and neuronal cell bodies in lobules VII and IX (crus I and II, ansiform lobules and tonsilla) and in the dentate nucleus. There is a significant presence of DAT immunoreactive dendritic arborization of the Purkinje neurons in the molecular layer of the human cerebellar cortex. Moreover, the DAT immunoreactivity has been detected in form of clusters in the neuropil among the space of Held, the sites of the cerebellar glomeruli. Furthermore, through different methods in the cerebellum of mammals, a wide distribution of the dopaminergic receptor subtypes (D1 to-D5) has been observed. A broad expression of all the dopaminergic receptor subtypes has been demonstrated in the rodent and human cerebellum. In the three layers of the cerebellar cortex, the dopaminergic receptor subtypes present a different distribution pattern.

In the molecular layer, immunoreactivity to D2, D3, and D5 receptors in the cell bodies and processes of stellate neurons, basket neurons, and in the dendritic arborizations of the Purkinje neurons has been detected. In the Purkinje neuron layer, D1, D2, D3, and D5 -positive cell bodies have been observed. In the granular layer, D2 immunoreactivity in the cell bodies and processes of granules, Golgi neurons, and in different non-traditional large neuron types of the granular layer distributed in three zones has been detected such as the Lugaro neuron, candelabrum neuron, the perivascular neuron in the external zone of the layer, the triangular neuron in the intermediate zone, the ellipsoidal neuron and the globular neuron in the internal zone. All dopaminergic areas of the cerebellum project towards the midbrain, the region of the brain that becomes ill in the case of diseases such as Parkinson’s disease, parkinsonism, multisystem atrophy and Huntington’s disease.

It is the same area that is affected by the side effects of anti-parkinsonian drugs: in the case of dopaminergic antagonism, tremor appears, the intensity and type of which is dictated by the functions of the cerebellum. Therefore, even if neurobiology does not consider the cerebellum as a primary dopaminergic cerebral region, it cannot be denied that it is at least secondary or in connection with it. Dopamine neurons are a major component of the brain reward system. By encoding motivational value and salience, they tighly regulate motivation, emotional states and social interactions. Although the regulation of these processes has been largely ascribed to neural circuits embedded in limbic regions, recent evidence indicate that the cerebellum, a region primarily involved in motor control, may also contribute to higher cognitive functions including social behaviors. However, whether cerebellar dopamine signaling could participate to the modulation of these functions remained unexplored.

An international research consortium including scientists from Inserm – University of Montpellier (France), the Institut de Neurociències Universitat Autònoma de Barcelona (Spain), and the University of Lausanne (Switzerland) has just published  research in the prestigious journal Nature Neuscience, describing how they uncovered how dopamine in the cerebellum modulates social behaviors via its action on D2 receptors (D2R). By using different mouse models and genetic tools, the researchers’ work shows that changes in D2R levels in a specific cerebellar cell type, the Purkinje cells, alter sociability and preference for social novelty without affecting motor functions. These new findings pave the way to determine whether socially related psychiatric disorders, such as bipolar mood disorder or schizophrenia, are also associated with altered dopamine receptors expression in specific cerebellar cell types. The researchers then went on to study their functions.

By using genetic approaches to invalidate or overexpress D2R selectively in Purkinje cells, they analyzed the impact of these alterations on motor and non-motor cerebellar functions. Reducing the expression of this specific dopamine receptor impaired the sociability of mice as well as their preference for social novelty, while their coordination and motor functions remained unaffected. This study constitutes a first step towards a better understanding of the role of dopamine in the cerebellum and the mechanisms underlying psychiatric disorders such as schizophrenia, ADHD and anxiety disorders, which have all in common aberrant dopamine signaling and altered social behaviors. Another area that will benefit out of the understanding of teh cerebellar dopamine network will be the autism and the autistic spectrum disorder (ASD), clinical condition where novelty is not seeked in favor of stereotypes and ripetitive and unchangeable behaviors.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

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Scientific references

Cutando L et al. Nature Neurosci. 2022 Jun 16 in press.

De Benedictis A et al. Front Neurol. 2022; 13:806298. 

Kishore A, Popa T. Front Neurol. 2014 Aug 18; 5:157. 

Rogers TD, Dickson P et al. Synapse. 2011; 65(11):1204. 

Mehler-Wex C et al. Neurotox Res. 2006; 10(3-4):167-79. 

Nieoullon A. Prog Neurobiol. 2002 May; 67(1):53-83.

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