A red-light-activated, optogenetic tool for studying brain plasticity could open new possibilities for the treatment of Huntington’s disease. Using an engineered, photoactivated adenylyl cyclase, researchers at the University of Barcelona, working with international institutions, investigated the role of astrocytes, a type of brain cell, and astrocytic cyclic adenosine monophosphate (cAMP) signaling in managing neuronal plasticity and brain network function. Synaptic plasticity — the brain’s ability to modify the connections between neurons to support learning and memory — is profoundly altered in Huntington’s disease. Although it is known that brain plasticity is affected by astrocytes, and specifically by astrocytic cAMP signaling, it is unclear how cAMP signaling might shape plasticity and cerebral functions. The image shows a section of the cerebral cortex, with astrocytes labeled in red, cell nuclei in blue, cells expressing the protein photoactivatable adenylate cyclase DdPAC (in green), and astrocytes expressing DdPAC (in yellow). The latter are the cells activated in response to red light. Courtesy of the University of Barcelona. The researchers analyzed the effects of cAMP levels in astrocytes in healthy mice and in mice with Huntington’s disease. The optogenetic tool allowed the team to modulate signaling pathways in the brain with precise spatial and temporal control. The researchers were able to modify cAMP levels in the mice in a controlled manner, in specific brain regions and cell types. “In this in vivo mouse model, we used a photoreceptor protein called photoactivatable adenylate cyclase (DdPAC), which can increase cAMP levels when illuminated with red light and deactivate them with far-infrared light, allowing for highly specific temporal and regional control of this pathway,” professor Mercè Masana, who led the research, said. The researchers performed a comprehensive analysis of molecular changes induced by DdPAC stimulation. They found that astrocytes played a far more active role in brain function and dysfunction than previously thought. When cAMP signaling was activated, the synaptic plasticity in the neurons was enhanced. Moreover, cortical astrocytic cAMP signaling was found to impact the brain at multiple functional levels. It affected synaptic potentiation and protein regulation. It also affected brain hemodynamics, increasing cortical blood flow, and behavior, improving motor learning. The researchers observed a more pronounced hemodynamic response in the Huntington’s disease mouse model than in the healthy mice. This finding indicated that the regulatory role of astrocytes in synaptic plasticity, particularly astrocytes involved in cAMP-dependent signaling, was disrupted by the presence of Huntington’s disease. This red-light-activated, optogenetic approach could contribute to the development of new therapeutic strategies, not only for Huntington’s disease, but also for other pathologies in which increased cAMP has beneficial effects on neuronal or glial function. “Since this signaling pathway is disrupted in many of these conditions, it could provide insight into how such imbalances contribute to brain dysfunction in each case,” Masana said. The optogenetic tool could also have a significant impact on the study of neuronal disorders. “Its main advantage over other photoreceptor proteins used in optogenetics, or over techniques such as chemogenetics, is that it enables highly precise temporal and spatial control, while also allowing modulation of more complex signaling pathways capable of long-term alterations in cellular function,” Masana said. “Furthermore, it has the potential for noninvasive application.” The research was published in iScience (www.doi.org/10.1016/j.isci.2025.113640).