Photoactivated adenylyl cyclase in cortical astrocytes promotes synaptic potentiation and reveals alterations in Huntington’s disease
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.
Authors
- Maryam Givehchi (ORCID: https://orcid.org/0009-0003-7625-9094)
- Alexander Bykov (ORCID: https://orcid.org/0000-0002-6228-6775)
- Edik U. Rafailov (ORCID: https://orcid.org/0000-0002-4152-0120)
- Deniz Dalkara (ORCID: https://orcid.org/0000-0003-4112-9321)
- Anna Castañé (ORCID: https://orcid.org/0000-0002-2578-445X)
- H. Rheinallt Parri (ORCID: https://orcid.org/0000-0002-1412-2688)
- Jordi Alberch (ORCID: https://orcid.org/0000-0002-8684-2721)
- Sara Conde-Berriozabal (ORCID: https://orcid.org/0000-0002-3712-8046)
- Laia Sitjà‐Roqueta
- Igor Meglinski (ORCID: https://orcid.org/0000-0002-7613-8191)
- Neville Ngum
- Melike Küçükerden (ORCID: https://orcid.org/0000-0002-4714-1666)
- Francis Delicata (ORCID: https://orcid.org/0000-0002-5339-5275)
- Mercè Masana (ORCID: https://orcid.org/0000-0003-1392-4774)
- Enrique Santamaría (ORCID: https://orcid.org/0000-0001-8046-8102)
- Manuel J. Rodrı́guez (ORCID: https://orcid.org/0000-0002-4476-004X)
- Joaquín Fernández‐Irigoyen (ORCID: https://orcid.org/0000-0001-5072-4099)
- Sergei G. Sokolovski (ORCID: https://orcid.org/0000-0001-7445-7204)
- Valentina Bova (ORCID: https://orcid.org/0000-0002-6927-8997)
- Andreas Möglich (ORCID: https://orcid.org/0000-0002-7382-2772)
- Elena Anaya‐Cubero (ORCID: https://orcid.org/0009-0000-0738-5896)
- Evgeny Zherebtsov (ORCID: https://orcid.org/0000-0002-3635-1430)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institut de la Vision (FR)
- Inserm (FR)
- Sorbonne Université (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- University of Bayreuth (DE)
- Universitat de Barcelona (ES)
- University of Oulu (FI)
Publication Details
- Journal
- iScience
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1016/j.isci.2025.113640
- Citations
- 1
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.91