MODULATION OF THE BIDIRECTIONAL COMMUNICATION BETWEEN NEURONS AND ASTROCYTES AT THE SYNAPSE: INFLUENCE OF BDNF AND P2 RECEPTORS

Funder

Organizational Unit

Publications

Publication . Oliveira, João F.; Gomes, Catarina A.; Vaz, Sandra H.; Sousa, Nuno; Pinto, Luisa

Depression is a highly prevalent disorder that poses a significant social burden to society. Despite continued advances toward the understanding of the pathophysiology of this disease, its molecular/cellular underpinnings remain elusive, which may be at the basis of the lack of effective treatment strategies. Among the different lines of research, recent literature suggests that impaired neuron and glial plasticity may be a key underlying mechanism in the precipitation of the disorder. Surprisingly, glial cells appear to be involved both in the pathophysiology of major depression and in the action of antidepressants. In particular, several works refer to alterations in the morphology and numbers of astrocytes, microglia, and oligodendrocytes in the context of depression, in human patients, and animal models of depression. These observations are linked to functional evidences, such as impairments in the cross-talk between glia and neurons, changes in the level of neurotransmitter or immunoactive substances, myelination status, and synapse formation, maintenance or elimination.

2016Journal article

Open access

Interaction between cannabinoid type 1 and type 2 receptors in the modulation of subventricular zone and dentate Gyrus neurogenesis

Publication . Rodrigues, Rui S.; Ribeiro, Filipa; Ferreira, Filipa; Vaz, Sandra H.; Sebastião, Ana M; Xapelli, Sara

Neurogenesis in the adult mammalian brain occurs mainly in two neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus (DG). Cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been shown to differently modulate neurogenesis. However, low attention has been given to the interaction between CB1R and CB2R in modulating postnatal neurogenesis (proliferation, neuronal differentiation and maturation). We focused on a putative crosstalk between CB1R and CB2R to modulate neurogenesis and cultured SVZ and DG stem/progenitor cells from early postnatal (P1-3) Sprague-Dawley rats. Data showed that the non-selective cannabinoid receptor agonist WIN55,212-2 promotes DG cell proliferation (measured by BrdU staining), an effect blocked by either CB1R or CB2R selective antagonists. Experiments with selective agonists showed that facilitation of DG cell proliferation requires co-activation of both CB1R and CB2R. Cell proliferation in the SVZ was not affected by the non-selective receptor agonist, but it was enhanced by CB1R selective activation. However, either CB1R or CB2R selective antagonists abolished the effect of the CB1R agonist in SVZ cell proliferation. Neuronal differentiation (measured by immunocytochemistry against neuronal markers of different stages and calcium imaging) was facilitated by WIN55,212-2 at both SVZ and DG. This effect was mimicked by either CB1R or CB2R selective agonists and blocked by either CB1R or CB2R selective antagonists, cross-antagonism being evident. In summary, our findings indicate a tight interaction between CB1R and CB2R to modulate neurogenesis in the two major neurogenic niches, thus contributing to further unraveling the mechanisms behind the action of endocannabinoids in the brain.

2017Journal article

Open access

Brain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effects

Publication . Mahú, Inês; Barateiro, Andreia; Rial-Pensado, Eva; Martinéz-Sánchez, Noelia; Vaz, Sandra H.; Cal, Pedro M.S.D.; Jenkins, Benjamin; Rodrigues, Tiago M.; Cordeiro, Carlos; Costa, Miguel F.; Mendes, Raquel; Seixas, Elsa; Pereira, Mafalda M.A.; Kubasova, Nadiya; Gres, Vitka; Morris, Imogen; Temporão, Carolina; Olivares, Marta; Sanz, Yolanda; Koulman, Albert; Corzana, Francisco; Sebastião, Ana M; López, Miguel; Bernardes, Gonçalo J. L.; Domingos, Ana I.

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.

2020Journal article

Open access

Modeling the functional network of primary intercellular Ca2+ wave propagation in astrocytes and its application to study drug effects

Publication . Pires, Marcelo; Raischel, Frank; Vaz, Sandra H.; Cruz Silva, Andreia; Sebastião, Ana M; Lind, Pedro G.

We introduce a simple procedure of multivariate signal analysis to uncover the functional connectivity among cells composing a living tissue and describe how to apply it for extracting insight on the effect of drugs in the tissue. The procedure is based on the covariance matrix of time resolved activity signals. By determining the time-lag that maximizes covariance, one derives the weight of the corresponding connection between cells. Introducing simple constraints, it is possible to conclude whether pairs of cells are functionally connected and in which direction. After testing the method against synthetic data we apply it to study intercellular propagation of Ca2+ waves in astrocytes following an external stimulus, with the aim of uncovering the functional cellular connectivity network. Our method proves to be particularly suited for this type of networking signal propagation where signals are pulse-like and have short time-delays, and is shown to be superior to standard methods, namely a multivariate Granger algorithm. Finally, based the statistical analysis of the connection weight distribution, we propose simple measures for assessing the impact of drugs on the functional connectivity between cells.

2013-11-27Journal article

Restricted access

Dysregulation of TrkB receptors and BDNF function by amyloid-β peptide is mediated by calpain

Publication . Jerónimo-Santos, André; Vaz, Sandra H.; Parreira, Sara; Lerias, Sofia; Caetano, António P.; Buée-Scherrer, Valérie; Castrén, Eero; Valente, Cláudia A.; Blum, David; Sebastião, Ana M; Diógenes, Maria José

Brain-derived neurotrophic factor (BDNF) and its high-affinity full-length (FL) receptor, TrkB-FL, play a central role in the nervous system by providing trophic support to neurons and regulating synaptic plasticity and memory. TrkB and BDNF signaling are impaired in Alzheimer's disease (AD), a neurodegenerative disease involving accumulation of amyloid-β (Aβ) peptide. We recently showed that Aβ leads to a decrease of TrkB-FL receptor and to an increase of truncated TrkB receptors by an unknown mechanism. In the present study, we found that (1) Aβ selectively increases mRNA levels for the truncated TrkB isoforms without affecting TrkB-FL mRNA levels, (2) Aβ induces a calpain-mediated cleavage on TrkB-FL receptors, downstream of Shc-binding site, originating a new truncated TrkB receptor (TrkB-T') and an intracellular fragment (TrkB-ICD), which is also detected in postmortem human brain samples, (3) Aβ impairs BDNF function in a calpain-dependent way, as assessed by the inability of BDNF to modulate neurotransmitter (GABA and glutamate) release from hippocampal nerve terminals, and long-term potentiation in hippocampal slices. It is concluded that Aβ-induced calpain activation leads to TrkB cleavage and impairment of BDNF neuromodulatory actions.

2015Journal article

Restricted access