Transient mGlu5R inhibition enhances the survival of granule cell precursors in the neonatal cerebellum

Kubera, Cathryn; Hernandez, Amanda; Heng, Vibol; Bordey, Angélique

doi:10.1016/j.neuroscience.2012.05.064

Cited by 4 publications

(4 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In C57BL mice at 9 days only few cells (<10 per 2 mm length of EGZ and <5 per 2 mm of granular layer) were TUNEL labeled (Wullner et al, 1995 ). A more recent study reported ~55000 TUNEL positive cells per mm 3 of EGZ in 9 day mouse cerebellum (Kubera et al, 2012 ). Where TUNEL positive cells in the mouse cerebellum have been counted, the proportion is typically low; e.g., <0.5% at 10 days in the EGZ (McNamee et al, 2002 ).…”

Section: Apoptosis Autophagy and Unfolded Protein Responsementioning

confidence: 96%

Cellular commitment in the developing cerebellum

Marzban

Bigio

Alizadeh

et al. 2015

Front. Cell. Neurosci.

152

139

View full text Add to dashboard Cite

The mammalian cerebellum is located in the posterior cranial fossa and is critical for motor coordination and non-motor functions including cognitive and emotional processes. The anatomical structure of cerebellum is distinct with a three-layered cortex. During development, neurogenesis and fate decisions of cerebellar primordium cells are orchestrated through tightly controlled molecular events involving multiple genetic pathways. In this review, we will highlight the anatomical structure of human and mouse cerebellum, the cellular composition of developing cerebellum, and the underlying gene expression programs involved in cell fate commitments in the cerebellum. A critical evaluation of the cell death literature suggests that apoptosis occurs in ~5% of cerebellar cells, most shortly after mitosis. Apoptosis and cellular autophagy likely play significant roles in cerebellar development, we provide a comprehensive discussion of their role in cerebellar development and organization. We also address the possible function of unfolded protein response in regulation of cerebellar neurogenesis. We discuss recent advancements in understanding the epigenetic signature of cerebellar compartments and possible connections between DNA methylation, microRNAs and cerebellar neurodegeneration. Finally, we discuss genetic diseases associated with cerebellar dysfunction and their role in the aging cerebellum.

show abstract

Section: Apoptosis Autophagy and Unfolded Protein Responsementioning

confidence: 96%

Cellular commitment in the developing cerebellum

Marzban

Bigio

Alizadeh

et al. 2015

Front. Cell. Neurosci.

152

139

View full text Add to dashboard Cite

show abstract

“…In an early study comparing the development of the P0-P9 cerebellum in normal and weaver mice, mitotic figures and pyknotic cells in the EGL were always very few in normal animals (2% and less than 0.5%, respectively), mainly located in the pre-migratory half of the EGL and, in Weaver , were quickly cleared from tissue in four-seven hours [33]. Later, using the TUNEL method and/or after direct TEM observation, several reports have been published that converged to demonstrate the presence of variable amounts of apoptotic CGCs in the P0–10 EGL of normal mice [11,69] and mutants such as Lurcher [70], Reeler [3,71], and Weaver [70]. However, few investigations were devoted to analyzing the relationship of CGC proliferation and NOND in this species.…”

Section: Caspase-3 In Cerebellar Developmentmentioning

confidence: 99%

Caspase-3 Mediated Cell Death in the Normal Development of the Mammalian Cerebellum

Lossi

Merighi

2018

IJMS

137

View full text Add to dashboard Cite

Caspase-3, onto which there is a convergence of the intrinsic and extrinsic apoptotic pathways, is the main executioner of apoptosis. We here review the current literature on the intervention of the protease in the execution of naturally occurring neuronal death (NOND) during cerebellar development. We will consider data on the most common altricial species (rat, mouse and rabbit), as well as humans. Among the different types of neurons and glia in cerebellum, there is ample evidence for an intervention of caspase-3 in the regulation of NOND of the post-mitotic cerebellar granule cells (CGCs) and Purkinje neurons, as a consequence of failure to establish proper synaptic contacts with target (secondary cell death). It seems possible that the GABAergic interneurons also undergo a similar type of secondary cell death, but the intervention of caspase-3 in this case still remains to be clarified in full. Remarkably, CGCs also undergo primary cell death at the precursor/pre-migratory stage of differentiation, in this instance without the intervention of caspase-3. Glial cells, as well, undergo a process of regulated cell death, but it seems possible that expression of caspase-3, at least in the Bergmann glia, is related to differentiation rather than death.

show abstract

“…One therapeutic area that has not been explored at length in patients is depression. This is somewhat surprising in light of the preclinical data supporting the notion that mGlu5 antagonists may correct behaviors associated with depression and that modulation of mGlu5 receptors may promote synaptic growth and plasticity (Kubera et al, 2012;Piers et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and secondgeneration antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wakepromoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

show abstract

Transient mGlu5R inhibition enhances the survival of granule cell precursors in the neonatal cerebellum

Cited by 4 publications

References 42 publications

Cellular commitment in the developing cerebellum

Cellular commitment in the developing cerebellum

Caspase-3 Mediated Cell Death in the Normal Development of the Mammalian Cerebellum

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Contact Info

Product

Resources

About