The interneurons of the olfactory bulb (OB) are characterized by the expression of different calcium-binding proteins, whose specific functions are not fully understood. This is the case of one of the most recently discovered, the secretagogin (SCGN), which is expressed in interneurons of the glomerular and the granule cell layers, but whose function in the olfactory pathway is still unknown. To address this question, we examined the distribution, generation and activity of SCGN-positive interneurons in the OB of two complementary models of olfactory impairments: Purkinje Cell Degeneration (PCD) and olfactory-deprived mice. Our results showed a significant increase in the density of SCGN-positive cells in the inframitral layers of olfactory-deprived mice as compared to control animals. Moreover, BrdU analyses revealed that these additional SCGN-positive cells are not newly formed. Finally, the neuronal activity, estimated by c-Fos expression, increased in preexisting SCGN-positive interneurons of both deprived and PCD mice -being higher in the later- in comparison with control animals. Altogether, our results suggest that the OB possesses different compensatory mechanisms depending on the type of alteration. Particularly, the SCGN expression is dependent of olfactory stimuli and its function may be related to a compensation against a reduction in sensory inputs.

In recent decades, the scientific community has faced a major challenge in the search for new therapies that can slow down or alleviate the process of neuronal death that accompanies neurodegenerative diseases. This study aimed to identify an effective therapy using neurotrophic factors to delay the rapid and aggressive cerebellar degeneration experienced by the Purkinje Cell Degeneration (PCD) mouse, a model of childhood-onset neurodegeneration with cerebellar atrophy (CONDCA). Initially, we analyzed the changes in the expression of several neurotrophic factors related to the degenerative process itself, identifying changes in insulin-like growth factor 1 (IGF-1) and Vascular Endothelial Growth Factor B (VEGF-B) in the affected animals. Then, we administered pharmacological treatments using human recombinant IGF-1 (rhIGF-1) or VEGF-B (rhVEGF-B) proteins, considering their temporal variations during the degenerative process. The effects of these treatments on motor, cognitive, and social behavior, as well as on cerebellar destructuration were analyzed. Whereas treatment with rhIGF-1 did not demonstrate any neuroprotective effect, rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice (and CONDCA patients). However, increasing the frequency of rhVEGF-B administration had a detrimental effect on Purkinje cell survival, suggesting an inverted U-shaped dose–response curve of this substance. Additionally, we demonstrate that this neuroprotective effect was achieved through a partial inhibition or delay of apoptosis. These findings provide strong evidence supporting the use of rhVEGF-B as a pharmacological agent to limit severe cerebellar neurodegenerative processes.

The cerebellar cortex presents a repetitive structure, but the main projecting neurons of this tissue, the Purkinje cells, are not identical and behave differently to various types of injury. Common patterns of neurodegeneration exist, where certain Purkinje cells die earlier than others. By contrast, lobe X of the cerebellum is a particularly resistant structure, independently of the cerebellar disease or damage. However, the mechanisms underlying the survival capability of these especially resistant Purkinje cells are still unknown. In this work, we have used the Purkinje Cell Degeneration (PCD) mouse, a model of severe cerebellar degeneration that also reproduces the human disease called childhood-onset neurodegeneration with cerebellar atrophy, to study Purkinje cell resistance. After an exhaustive immunochemical analysis of the different subpopulations of Purkinje cells, the Heat Shock Protein 25 (HSP25) and its phosphorylated version HSP25-P-Ser15 were found to be especially induced in lobe X of PCD mice. As this protein has neuroprotective properties, it may be responsible for resistance against cerebellar neurodegeneration. Taking into account the constant resistance of lobe X, the use of HSP25 may lead to new possibilities for achieving natural protection both in cerebellum and in other brain structures, or even for developing future neuroprotective therapies.

Introduction: Calcium is essential for the correct functioning of the central nervous system, and calcium-binding proteins help to finely regulate its concentration. Whereas some calcium-binding proteins such as calmodulin are ubiquitous and are present in many cell types, others such as calbindin, calretinin, and parvalbumin are expressed in specific neuronal populations. Secretagogin belongs to this latter group and its distribution throughout the brain is only partially known. In the present work, the distribution of secretagogin-immunopositive cells was studied in the entire brain of healthy adult mice.Methods: Adult male C57BL/DBA mice aged between 5 and 7 months were used. Their whole brain was sectioned and used for immunohistochemistry. Specific neural populations were observed in different zones and nuclei identified according to Paxinos mouse brain atlas.Results: Labelled cells were found with a Golgi-like staining, allowing an excellent characterization of their dendritic and axonal arborizations. Many secretagogin-positive cells were observed along different encephalic regions, especially in the olfactory bulb, basal ganglia, and hypothalamus. Immunostained populations were very heterogenous in both size and distribution, as some nuclei presented labelling in their entire extension, but in others, only scattered cells were present.Discussion: Secretagogin can provide a more complete vision of calcium-buffering mechanisms in the brain, and can be a useful neuronal marker in different brain areas for specific populations.

In recent decades, the scientific community has faced a major challenge in the search for new therapies that can slow down or alleviate the process of neuronal death that accompanies neurodegenerative diseases. This study aimed at identifying an effective therapy using neurotrophic factors to delay the rapid and aggressive cerebellar degeneration experienced by the Purkinje Cell Degeneration (PCD) mouse, a model of childhood-onset neurodegeneration with cerebellar atrophy (CONDCA). Initially, we analyzed the changes in the expression of several neurotrophic factors related to the degenerative process itself, identifying changes in insulin-like growth factor 1 (IGF-1) and Vascular Endothelial Growth Factor B (VEGF-B) in the affected animals. Then, we administered pharmacological treatments using human recombinant IGF-1 (rhIGF-1) or VEGF-B (rhVEGF-B) proteins, considering their temporal variations during the degenerative process. The effects of these treatments on motor, cognitive, and social behavior, as well as on cerebellar destructuration were analyzed. Whereas treatment with rhIGF-1 did not demonstrate any neuroprotective effect, rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice (and CONDCA patients). Additionally, we demonstrate that this neuroprotective effect was achieved through a partial inhibition or delay of apoptosis. These findings provide strong evidence supporting the use of rhVEGF-B as a pharmacological agent to limit severe cerebellar neurodegenerative processes.

SUMMARY: Bone marrow-derived cells (BMDCs) can infiltrate the brain and adopt new identities through transdifferentiation or fusion, yet their interactions with specific neural cells remain poorly defined. We examined BMDC fusion with Bergmann glia (BG), a key cerebellar support cell, in a mouse model of multiple sclerosis. After bone marrow transplantation, BMDCs fused with BG to form heterokaryons, retaining BG morphology and molecular markers. These heterokaryons contained donor and host nuclei that differed in both morphology and transcriptional activity. Remarkably, the BMDC nucleus localized not only to the soma but also along BG processes. This discovery identifies BMDC-BG fusion as a previously unrecognized form of glial plasticity, opening avenues for therapeutic strategies aimed at potentiating glial- mediated repair.