Delineating the Factors and Cellular Mechanisms Involved in the Survival of Cerebellar Granule Neurons

Abstract

Cerebellar granule neurons (CGNs) constitute the most abundant neuronal population in the mammalian brain. Their postnatal generation and the feasibility to induce their apoptotic death in vitro make them an excellent model to study the effect of several neurotransmitters and neurotrophins. Here, we first review which factors are involved in the generation and proliferation of CGNs in the external granule layer (EGL) and in the regulation of their differentiation and migration to internal granule layer (IGL). Special attention was given to the role of several neurotrophins and the NMDA subtype of glutamate receptor. Then, using the paradigm of potassium deprivation in cultured CGNs, we address several extracellular factors that promote the survival of CGNs, with particular emphasis on the cellular mechanisms. The role of specific protein kinases leading to the regulation of transcription factors and recent data involving the small G protein family is also discussed. Finally, the participation of some members of Bcl-2 family and the inhibition of mitochondria-related apoptotic pathway is also considered. Altogether, these studies evidence that CGNs are a key model to understand the development and the survival of neuronal populations.

METTL3-mediated m6A modification is required for cerebellar development

“…More specifically, we found that genes associated with the two major glutamate receptors, the N-methyl-D-aspartic acid (NMDA) receptors and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were highly enriched in the pathway analysis ( Fig 6B ). NMDA receptors were reported to be essential for the maturation and survival of CGCs [ 44 , 45 ]. We confirmed that the m 6 A-modified exons ( S8B and S8C Fig ) in these synapse-associated genes, such as Grin1 , Atp2b3 , Grm1 , and Lrp8 , were excluded in cKO cerebellums by RT-PCR ( Fig 6C and S9C Fig ).…”

A Novel Tetramethylpyrazine Derivative Prophylactically Protects against Glutamate-Induced Excitotoxicity in Primary Neurons through the Blockage of N-Methyl-D-aspartate Receptor

“…Similarly, primary CGNs that well express NMDA receptors are widely used in the field of neuroscience and neuropharmacology ( Contestabile, 2002 ; Xifro and Rodriguez-Alvarez, 2015 ). These cells are popular because it is easy, in vitro , to acquire abundant and homogeneous CGNs (over 95% are CGNs in the cerebellum) from the explanted cerebellum than other neurons (hippocampal and cortical neurons).…”