A carregar...
Projeto de investigação
Sem título
Financiador
Autores
Publicações
Adenosine receptors are the on‐and‐off switch of astrocytic cannabinoid type 1 (CB1) receptor effect upon synaptic plasticity in the medial prefrontal cortex
Publication . Gonçalves-Ribeiro, Joana; Savchak, Oksana K.; Pinto, Sara; Gomes, Joana I.; Rivas‐Santisteban, Rafael; Lillo, Alejandro; Sánchez Romero, Javier; Sebastião, Ana M; Navarrete, Marta; Navarro, Gemma; Franco, Rafael; Vaz, Sandra H.
The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca2+) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A1 and A2A receptors (A1R, A2AR), being unknown the crosstalk between CB1R and adenosine receptors in these cells. We show here that a further level of regulation of astrocyte Ca2+ signaling occurs through CB1R-A2AR or CB1R-A1R heteromers that ultimately impact mPFC synaptic plasticity. CB1R-mediated Ca2+ transients increased and decreased when A1R and A2AR were activated, respectively, unveiling adenosine receptors as modulators of astrocytic CB1R. CB1R activation leads to an enhancement of long-term potentiation (LTP) in the mPFC, under the control of A1R but not of A2AR. Notably, in IP3R2KO mice, that do not show astrocytic Ca2+ level elevations, CB1R activation decreases LTP, which is not modified by A1R or A2AR. The present work suggests that CB1R has a homeostatic role on mPFC LTP, under the control of A1R, probably due to physical crosstalk between these receptors in astrocytes that ultimately alters CB1R Ca2+ signaling.
The IP3R2 knockout mice in behavior: a blessing or a curse?
Publication . Gonçalves-Ribeiro, Joana; Vaz, Sandra H.
The inositol 1,4,5-triphosphate receptor type 2 (IP3R2) plays a critical role in intracellular calcium (Ca2+) signaling, particularly in astrocytes, where it mediates Ca2+ release from the endoplasmic reticulum. This mechanism is vital for astrocytic modulation of neuronal networks, impacting synaptic transmission and broader neural circuit functions. The IP3R2 knockout (IP3R2KO) mouse model has been instrumental in unraveling the nuances of astrocytic somatic Ca2+ dynamics and their implications for brain function. Despite early findings suggesting no significant behavioral or synaptic transmission changes in IP3R2KO mice, further research highlights the model's benefit in exploring cognitive, emotional, and neurodevelopmental processes. IP3R2KO mice revealed key insights into astrocytic Ca2+ signaling diversity, encompassing bulk somatic events and localized microdomain responses, which exhibit temporal and spatial variability. These animals retain alternative Ca2+ mechanisms, likely explaining the absence of severe phenotypes in some contexts. Nevertheless, IP3R2KO mice exhibit impairments in long-term memory retention, working memory, and fear memory, alongside age-related preservation of spatial memory, linking astrocytic IP3R2 signaling to higher-order cognitive functions. Additionally, studies suggest a connection between IP3R2 pathways and depression-like behaviors, with alterations in Brain-Derived Neurotrophic Factor (BDNF) levels and GABAergic signaling, highlighting its relevance to psychiatric conditions. Despite its limitations, such as residual astrocytic Ca2+ activity and inconsistent findings, the IP3R2KO model remains a valuable tool for studying astrocytic contributions to synaptic plasticity and brain function. This underscores the importance of integrating, rather than dismissing, the IP3R2KO model in the development of new methodologies for studying astrocytic Ca2+ dynamics. The use of this model will continue to elucidate the complex interplay between astrocytes and neuronal circuits, fostering advances in understanding astrocytic Ca2+ signaling's role in health and disease.
Unidades organizacionais
Descrição
Palavras-chave
Contribuidores
Financiadores
Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
Número da atribuição
PD/BD/150342/2019