Photoactivated Adenylyl Cyclase in Cortical Astrocytes Promotes Synaptic Potentiation and Reveals Alterations in Huntington’s Disease

Laia Sitjà-Roqueta; Neville M. Ngum; Evgenii Zherebstov; 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

doi:10.1016/j.isci.2025.113640

Photoactivated Adenylyl Cyclase in Cortical Astrocytes Promotes Synaptic Potentiation and Reveals Alterations in Huntington’s Disease

Laia Sitjà-Roqueta
, Neville M. Ngum
, Evgenii Zherebstov
, 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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. Modulation of astrocytic cAMP triggered long-term synaptic potentiation and rapidly induced 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 signalling associated with HD.

Original language	English
Article number	113640
Number of pages	23
Journal	iScience
Volume	28
Issue number	11
Early online date	23 Sept 2025
DOIs	https://doi.org/10.1016/j.isci.2025.113640
Publication status	Published - 21 Nov 2025

Bibliographical note

Copyright © 2025 Published by Elsevier Inc. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Funding

This research is part of the NEUROPA and GlioLight project. The NEUROPA Project has received funding from the European Union’s Horizon 2020 Research and Innovation Program under Grant Agreement No. 863214. The GlioLight project has received funding from the European Innovation Council under grant Agreement 101129705. The Aston Institute for Membrane Excellence (AIME) is funded by UKRI’s Research England as part of their Expanding Excellence in England (E3) fund. MK is funded by Horizon Europe Marie Skłodowska-Curie Actions (101104889). This study was supported by grants from the Ministerio de Ciencia y Innovación (Spain) y la Agencia Estatal de Investigación, under projects CNS2023-143999 (MM.), PID2021-124896OA-I00 (M.M.), and no. PID2020-119386RB-I00 (J.A. and M.J.R.); Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades and European Regional Development Fund (ERDF) [CIBERNED, to J.A.], Spain. Also, the project has been supported by María de Maeztu Unit of Excellence (CEX2021-001159), the Institute of Neurosciences of the University of Barcelona, Ministry of Science, Innovation, and Universities, and the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR, Catalunya) (2021SGR01086).

Keywords

Model organism
Neuroscience

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10.1016/j.isci.2025.113640Licence: CC BY 4.0

Photoactivated Adenylyl Cyclase in Cortical Astrocytes Promotes Synaptic Potentiation and Reveals Alterations in Huntington’s Disease
Copyright © 2025 The Authors. Published by Elsevier Inc. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Final published version, 11.5 MBLicence: CC BY 4.0

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Sitjà-Roqueta, L., Ngum, N. M., Zherebstov, E., Küçükerden, M., Givehchi, M., Bova, V., Delicata, F., Anaya-Cubero, E., Santamaria, E., Fernández-Irigoyen, J., Conde-Berriozabal, S., Castañé, A., Sokolovski, S., Rafailov, E., Rodríguez, M. J., Alberch, J., Dalkara, D., Möglich, A., Bykov, A., ... Masana, M. (2025). Photoactivated Adenylyl Cyclase in Cortical Astrocytes Promotes Synaptic Potentiation and Reveals Alterations in Huntington’s Disease. iScience, 28(11), Article 113640. https://doi.org/10.1016/j.isci.2025.113640

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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. Modulation of astrocytic cAMP triggered long-term synaptic potentiation and rapidly induced phosphorylation of proteins involved in synaptic transmission, including PKA. In Huntington{\textquoteright}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 signalling associated with HD.",

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Sitjà-Roqueta, L, Ngum, NM, Zherebstov, E, Küçükerden, M, Givehchi, M, Bova, V, Delicata, F, Anaya-Cubero, E, Santamaria, E, Fernández-Irigoyen, J, Conde-Berriozabal, S, Castañé, A, Sokolovski, S , Rafailov, E, Rodríguez, MJ, Alberch, J, Dalkara, D, Möglich, A, Bykov, A, Meglinski, I , Parri, HR & Masana, M 2025, 'Photoactivated Adenylyl Cyclase in Cortical Astrocytes Promotes Synaptic Potentiation and Reveals Alterations in Huntington’s Disease', iScience, vol. 28, no. 11, 113640. https://doi.org/10.1016/j.isci.2025.113640

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T1 - Photoactivated Adenylyl Cyclase in Cortical Astrocytes Promotes Synaptic Potentiation and Reveals Alterations in Huntington’s Disease

AU - Sitjà-Roqueta, Laia

AU - Ngum, Neville M.

AU - Zherebstov, Evgenii

AU - Küçükerden, Melike

AU - Givehchi, Maryam

AU - Bova, Valentina

AU - Delicata, Francis

AU - Anaya-Cubero, Elena

AU - Santamaria, Enrique

AU - Fernández-Irigoyen, Joaquín

AU - Conde-Berriozabal, Sara

AU - Castañé, Anna

AU - Sokolovski, Sergei

AU - Rafailov, Edik

AU - Rodríguez, Manuel J.

AU - Alberch, Jordi

AU - Dalkara, Deniz

AU - Möglich, Andreas

AU - Bykov, Alexander

AU - Meglinski, Igor

AU - Parri, H.Rheinallt

AU - Masana, Mercè

N1 - Copyright © 2025 Published by Elsevier Inc. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PY - 2025/11/21

Y1 - 2025/11/21

N2 - 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. Modulation of astrocytic cAMP triggered long-term synaptic potentiation and rapidly induced 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 signalling associated with HD.

AB - 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. Modulation of astrocytic cAMP triggered long-term synaptic potentiation and rapidly induced 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 signalling associated with HD.

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Photoactivated Adenylyl Cyclase in Cortical Astrocytes Promotes Synaptic Potentiation and Reveals Alterations in Huntington’s Disease

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