Photoactivated adenylyl cyclase in cortical astrocytes promotes synaptic potentiation and reveals alterations in Huntington’s disease
Year: 2025
Type: article
Abstract: Coordinated neuron-astrocyte interactions are crucial for synaptic plasticity and brain function. Cyclic adenosine monophosphate (cAMP) pathways have a key role in modulating plasticity and are disrupted in neurodegenerative diseases. Yet, the role of astrocytic cAMP remains unclear. We addressed this by expressing the photoactivatable adenylyl cyclase DdPAC in cortical astrocytes, enabling cAMP synthesis under red light stimulation. Using electrophysiological and comprehensive proteomic analyses, we determined its effects in wild-type mice. The modulation of astrocytic cAMP triggered long-term synaptic potentiation and rapidly induced the phosphorylation of proteins involved in synaptic transmission, including PKA. In Huntington's Disease (HD) models, DdPAC activation in cortical astrocytes differentially enhanced brain hemodynamics and induced motor learning, while specifically increasing grooming and impairing coordination in HD mice. Thus, we reveal a mechanism of astrocyte-driven plasticity mediated by cAMP elevation and underscore the alterations in astrocytic cAMP signaling associated with HD.
Source: iScience
Authors: Laia Sitjà-Roqueta, Neville M. Ngum, Evgenii A. Zherebtsov, Melike Küçükerden, Maryam Givehchi, Valentina Bova, Francis Delicata, Elena Anaya-Cubero, Enrique Santamaria, Joaquín Fernández-Irigoyen, Sara Conde-Berriozabal, Anna Castañé, Sergei Sokolovski, Edik Rafailov, Manuel J. Rodríguez, Jordi Alberch, Deniz Dalkara, Andreas Möglich, Alexander Bykov, Igor Meglinski, H. Rheinallt Parri, Mercè Masana
Institutions: Biomedical Research Networking Center on Neurodegenerative Diseases, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Aston University, University of Oulu, Universidad Pública de Navarra (UPNA), Navarre Institute of Health Research, Navarrabiomed, Universitat de Vic - Universitat Central de Catalunya, Centre National de la Recherche Scientifique, Institut de la Vision, Inserm, Sorbonne Université, University of Bayreuth
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
Funders: University of Minnesota, UK Research and Innovation, Ministerio de Ciencia, Innovación y Universidades, Ministerio de Ciencia e Innovación, Universitat de Barcelona, University of California, San Diego, Horizon 2020 Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Horizon 2020, European Regional Development Fund, Agencia Estatal de Investigación, Research England, H2020 Marie Skłodowska-Curie Actions, HORIZON EUROPE Marie Sklodowska-Curie Actions, HORIZON EUROPE European Innovation Council
OpenAlex ID: W4414517209