Deciphering New Players in the Neurogenic Adult Hippocampal Niche

In the mammalian adult hippocampus, new neurons are continuously generated throughout life in the subgranular zone of the dentate gyrus. Increasing evidence point out the contribution of adult-born hippocampal granule cells (GCs) to cognitive processes such as learning and memory, indicating the relevance of understanding the molecular mechanisms that control the development of these new neurons in the preexisting hippocampal circuits. Cell proliferation and functional integration of adult-born GCs is a process highly regulated by different intrinsic and extrinsic factors. In this review, we discuss recent advances related with cellular components and extrinsic signals of the hippocampal neurogenic niche that support and modulate neurogenesis under physiological conditions.Fil: Bonafina, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Paratcha, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Ledda, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

The GDNF-GFRα1 complex promotes the development of hippocampal dendritic arbors and spines via NCAM

The formation of synaptic connections during nervous system development requires the precise control of dendrite growth and synapse formation. Although glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRα1 are expressed in the forebrain, the role of this system in the hippocampus remains unclear. Here, we investigated the consequences of GFRα1 deficiency for the development of hippocampal connections. Analysis of conditional Gfra1 knockout mice shows a reduction in dendritic length and complexity, as well as a decrease in postsynaptic density specializations and in the synaptic localization of postsynaptic proteins in hippocampal neurons. Gain- and loss-of-function assays demonstrate that the GDNF-GFRα1 complex promotes dendritic growth and postsynaptic differentiation in cultured hippocampal neurons. Finally, in vitro assays revealed that GDNF-GFRα1- induced dendrite growth and spine formation are mediated by NCAM signaling. Taken together, our results indicate that the GDNF-GFRα1 complex is essential for proper hippocampal circuit development.Fil: Irala, Dolores. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Bonafina, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Fontanet, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Alsina, Fernando Cruz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Paratcha, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Ledda, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Differential Hippocampal Expression of BDNF Isoforms and Their Receptors Under Diverse Configurations of the Serotonergic System in a Mice Model of Increased Neuronal Survival

Neurotrophic factors are relevant regulators of the neurogenic process at different levels. In particular, the brain-derived neurotrophic factor, BDNF, is highly expressed in the hippocampus (HC) of rodents and participates in the control of neuronal proliferation, and survival in the dentate gyrus (DG). Likewise, serotonin is also involved in the regulation of neurogenesis, though its role is apparently more complex. Indeed, both enhancement of serotonin neurotransmission as well as serotonin depletion, paradoxically increase neuronal survival in the HC of mice. In this study, we analyzed the protein expression of the BDNF isoforms, i.e., pro- and mature-BDNF, and their respective receptors p75 and TrkB, in the HC of mice chronically treated with para-chloro-phenyl-alanine (PCPA), an inhibitor of serotonin synthesis. The same analysis was conducted in hyposerotonergic mice with concomitant administration of the 5-HT1 A receptor agonist, 8-Hydroxy-2-(di-n- propylamino) tetralin (8-OH-DPAT). Increased expression of p75 receptor with decreased expression of pro-BDNF was observed after chronic PCPA. Seven-day treatment with 8-OH-DPAT reestablished the expression of pro-BDNF modified by PCPA, and induced an increase in the expression of p75 receptor. It has been demonstrated that PCPA-treated mice have higher number of immature neurons in the HC. Given that immature neurons participate in the pattern separation process, the object pattern separation test was conducted. A better performance of hyposerotonergic mice was not confirmed in this assay. Altogether, our results show that molecules in the BDNF signaling pathway are differentially expressed under diverse configurations of the serotonergic system, allowing for fine-tuning of the neurogenic process.Fil: Foltran, Rocío Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Stefani, Karen Melany. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Bonafina, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Resasco, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Diaz, Silvina Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

GDNF and GFRα1 Are Required for Proper Integration of Adult-Born Hippocampal Neurons

The glial cell line-derived neurotrophic factor (GDNF) is required for the survival and differentiation of diverse neuronal populations during nervous system development. Despite the high expression of GDNF and its receptor GFRα1 in the adult hippocampus, the functional role of this system remains unknown. Here, we show that GDNF, acting through its GFRα1 receptor, controls dendritic structure and spine density of adult-born granule cells, which reveals that GFRα1 is required for their integration into preexisting circuits. Moreover, conditional mutant mice for GFRα1 show deficits in behavioral pattern separation, a task in which adult neurogenesis is known to play a critical role. We also find that running increases GDNF in the dentate gyrus and promotes GFRα1-dependent CREB (cAMP response element-binding protein) activation and dendrite maturation. Together, these findings indicate that GDNF/GFRα1 signaling plays an essential role in the plasticity of adult circuits, controlling the integration of newly generated neurons.Fil: Bonafina, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Trinchero, Mariela Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Rios, Antonella Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Bekinschtein, Pedro Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt; ArgentinaFil: Schinder, Alejandro Fabián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Paratcha, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Ledda, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Role of the GDNF / GFRa1 system in the development and maturation of neuronal precursors

During development, neural stem cells (NSCs) and their derivative progenitor cells give rise to all the neurons of the central nervous system, with only a few neurogenic zones remaining active in the adult. Because impaired regulation of progenitors causes many developmental disorders, it is crucial to understand the mechanisms underlying the behavior of progenitors including migration, proliferation, and differentiation. The transition of proliferative progenitor cells to fully differentiated neurons is controlled by an intrinsic cellular program, as well as extrinsic environmental cues, such as neurotrophic factors. Neurotrophic factors play key roles in the maintenance and survival of different neuronal populations in the peripheral and central nervous system. Glial cell line-derived neurotrophic factor (GDNF) was originally discovered because of its ability to promote the survival of ventral midbrain dopaminergic neurons, those affected in Parkinson´s disease. GDNF signals by binding to the glycosylphosphatidylinositolanchored receptor GFRα1 in complex with the canonic receptor tyrosine kinase Ret or the neural cell adhesion molecule (NCAM). The aim of this thesis was to identify and analyze new roles of GDNF and its receptors during the proliferation and differentiation of neural progenitors both in the developing as in the adult nervous system. To start analyzing the role of GDNF and its receptor GFRα1 in cortical neurogenesis, GFRα1 expression was analyzed in the forebrain during development. It was found that GFRα1 is expressed from an early developmental stage, increasing its levels in inverse proportion to the levels of the mitogenic factor, bFGF. Furthermore, it was observed that the expression levels of GFRα1 correlated with neuronal differentiation of cortical precursors. The addition of GDNF to cultures of neuronal precursors decreased the proliferation rate of the progenitors and increased morphological differentiation of postmitotic neurons. Analysis of animals deficient for GFRα1 in neuronal precursors show lower neuritic complexity of cortical neurons, and an increase in proliferation rate of progenitors in vivo. Taken together, these results show that GDNF may be playing an antagonistic role to bFGF on cortical precursors. This would indicate that the GDNF / 11 GFRα1 system plays an essential role in regulating the proliferative condition and the differentiation of cortical progenitors. On the other hand, the role of the GDNF/GFRα1 system in adult neurogenesis was analyzed. It was found that GFRα1 is highly expressed in the dentate gyrus of the hippocampus, a neurogenic zone. Adult born granule neurons derived from mice deficient in GFRα1 in neuronal progenitors of the adult hippocampus showed lower neuritic complexity than those observed in control mice neurons. Ablation of GFRα1 in adult hippocampal progenitors was associated with behavioral deficits, providing new insights into its physiological importance. In conclusion, in this manuscript new physiological roles of GDNF and its receptor, GFRα1, were identified. Cortical and adult progenitors share certain characteristics and differ in others, however the GDNF/GFRα1 system may act as a general regulator coordinating neuronal differentiation

GDNF/GFRα1 Complex Abrogates Self-Renewing Activity of Cortical Neural Precursors Inducing Their Differentiation

The balance between factors leading to proliferation and differentiation of cortical neural precursors (CNPs) determines the correct cortical development. In this work, we show that GDNF and its receptor GFRα1 are expressed in the neocortex during the period of cortical neurogenesis. We show that the GDNF/GFRα1 complex inhibits the self-renewal capacity of mouse CNP cells induced by fibroblast growth factor 2 (FGF2), promoting neuronal differentiation. While GDNF leads to decreased proliferation of cultured cortical precursor cells, ablation of GFRα1 in glutamatergic cortical precursors enhances its proliferation. We show that GDNF treatment of CNPs promoted morphological differentiation even in the presence of the self-renewal-promoting factor, FGF2. Analysis of GFRα1-deficient mice shows an increase in the number of cycling cells during cortical development and a reduction in dendrite development of cortical GFRα1-expressing neurons. Together, these results indicate that GDNF/GFRα1 signaling plays an essential role in regulating the proliferative condition and the differentiation of cortical progenitors. In this article, Ledda and colleagues show that GDNF acting through its receptor GFRα1 plays a critical role in the maturation of cortical progenitors by counteracting FGF2 self-renewal activity on neural stem cells and promoting neuronal differentiation.Fil: Bonafina, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Fontanet, Paula Aldana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Paratcha, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Ledda, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin