Transcriptome programs involved in the development and structure of the cerebellum

In the past two decades, mounting evidence has modified the classical view of the cerebellum as a brain region specifically involved in the modulation of motor functions. Indeed, clinical studies and engineered mouse models have highlighted cerebellar circuits implicated in cognitive functions and behavior. Furthermore, it is now clear that insults occurring in specific time windows of cerebellar development can affect cognitive performance later in life and are associated with neurological syndromes, such as Autism Spectrum Disorder. Despite its almost homogenous cytoarchitecture, how cerebellar circuits form and function is not completely elucidated yet. Notably, the apparently simple neuronal organization of the cerebellum, in which Purkinje cells represent the only output, hides an elevated functional diversity even within the same neuronal population. Such complexity is the result of the integration of intrinsic morphogenetic programs and extracellular cues from the surrounding environment, which impact on the regulation of the transcriptome of cerebellar neurons. In this review, we briefly summarize key features of the development and structure of the cerebellum before focusing on the pathways involved in the acquisition of the cerebellar neuron identity. We focus on gene expression and mRNA processing programs, including mRNA methylation, trafficking and splicing, that are set in motion during cerebellar development and participate to its physiology. These programs are likely to add new layers of complexity and versatility that are fundamental for the adaptability of cerebellar neurons.

Physiological and Morphological Principles Underpinning Recruitment of the Cerebellar Reserve

Background: In order to optimize outcomes of novel therapies for cerebellar ataxias (CAs), it is desirable to start these therapies while declined functions are restorable: i.e. while the so-called cerebellar reserve remains. Objective: In this mini-review, we tried to define and discuss the cerebellar reserve from physiological and morphological points of view. Method: The cerebellar neuron circuitry is designed to generate spatiotemporally organized outputs, regardless of the region. Therefore, the cerebellar reserve may be defined as a mechanism to restore its proper input-output organization of the cerebellar neuron circuitry, when it is damaged. Then, the following four components are essential for recruitment of the cerebellar reserve: operational local neuron circuitry; proper combination of mossy fiber inputs to be integrated; climbing fiber inputs to instruct favorable reorganization of the integration; deep cerebellar nuclei to generate reorganized outputs. Results: We discussed three topics related to these resources, 1) principles of generating organized cerebellar outputs, 2) redundant mossy fiber inputs to the cerebellum, 3) plasticity of the cerebellar neuron circuitry. Conclusion: To make most of the cerebellar reserve, it is desirable to start any intervention as early as possible when the cerebellar cell loss is minimal or even negligible. Therefore, an ideal future therapy for degenerative cerebellar diseases should start before consuming the cerebellar reserve at all. In the meantime, our real challenge is to establish a reliable method to identify the decrease in the cerebellar reserve as early as possible.

Neurosteroid Biosynthesis and Action in the Purkinje Cell

It is now clearly established that steroids can be synthesized de novo by the vertebrate brain. Such steroids are called neurosteroids. To understand neurosteroid action in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed. In the middle 1990s, the Purkinje cell, an important cerebellar neuron, was identified as a major site for neurosteroid formation in vertebrates. This discovery has allowed deeper insights into neuronal neurosteroidogenesis and biological actions of neurosteroids have become clear by the studies using the Purkinje cell as an excellent cellular model, which is known to play an important role in memory and learning processes. From the past 10 years of research on mammals, we now know that the Purkinje cell actively synthesizes progesterone and estradiol de novo from cholesterol during neonatal life, when cerebellar neuronal circuit formation occurs. Both progesterone and estradiol promote dendritic growth, spinogenesis, and synaptogenesis via each cognate nuclear receptor in the developing Purkinje cell. Such neurosteroid actions that may be mediated by neurotrophic factors contribute to the formation of cerebellar neuronal circuit during neonatal life. Allopregnanolone, a progesterone metabolite, is also synthesized in the cerebellum and acts on Purkinje cell survival in the neonate. The aim of this review is to summarize the current knowledge regarding the biosynthesis and biological actions of neurosteroids in the Purkinje cell during development.