This innovative optogenetic technique allows for highly precise control of a key molecular mechanism that is altered in this neurodegenerative disease.
Synaptic plasticity - the brain's ability to modify the connections between neurons to support learning - is one of the neural functions profoundly altered in Huntington's disease, with a direct impact on brain function. Researchers at the University of Barcelona used an innovative optogenetic tool to show that astrocytes, a type of brain cell traditionally considered to play a supporting role, also influence this plasticity and are themselves altered in Huntington's disease. These results, obtained in animal models, open up new avenues for addressing this genetically driven neurodegenerative disease in patients.
The study, published in the journal iScience , is led by Mercè Masana, professor at the UB's Faculty of Medicine and Health Sciences and researcher at the Institute of Neurosciences (UBneuro), the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), and the CIBER Area for Neurodegenerative Diseases (CIBERNED). Researchers from the University of Vic-Central University of Catalonia (UVic-UCC), the Navarrabiomed Proteomics Platform, Aston University (Birmingham, United Kingdom), the University of Oulu (Oulu, Finland), the Vision Institute (Paris, France), and the University of Bayreuth (Bayreuth, Germany) also participated in the study.
Optogenetics to decipher mechanisms of brain dysfunction
Synaptic plasticity depends largely on cyclic adenosine monophosphate (cAMP) signalling, but the role of astrocytic cAMP in this process remains unknown. To address this question, the researchers analysed the effects of this molecule in astrocytes from healthy mice and from a mouse model of Huntington's disease, using an optogenetic tool that enables light-controlled regulation of these molecules in complex organisms for the first time.
"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," says Mercè Masana.
The results show that cAMP activation in astrocytes enhances synaptic plasticity in neurons. In addition, the researchers found that selective manipulation of this signalling pathway in cortical astrocytes has "an impact at many levels: molecular, with changes at the protein level; cellular, with glutamate release and neuronal potentiation; at the cellular circuit level, with increased cortical blood flow, and at the behavioural level, with improved motor learning," the researcher notes.
Differences were also observed in the Huntington's disease mouse model, such as a more pronounced hemodynamic response than in healthy animals. According to the research team, these findings indicate that astrocytes - particularly cAMP-dependent signalling - do not respond as they normally would, and that their regulatory role in synaptic plasticity is disrupted in Huntington's disease.
According to the researchers, these findings highlight that "astrocytes play a far more active role than previously thought in both brain function and dysfunction, and that understanding how cAMP signalling is altered in these processes could
open new avenues for the development of more targeted and effective therapies for Huntington's disease."
A common pathway in multiple neurodegenerative diseases
This study could have important implications for a range of neurodegenerative diseases. "Since this signalling pathway is disrupted in many of these conditions, it could provide insight into how such imbalances contribute to brain dysfunction in each case," says Masana.
The optogenetic tool used in this study may also have a significant impact in the field. "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 signalling pathways capable of long-term alterations in cellular function. Furthermore, it has the potential for non-invasive application," the researcher notes.
These characteristics make it possible to modulate cAMP levels in a controlled manner in specific regions or cell types, "an approach that 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," the researcher concludes.
