Researchers at the University of Barcelona have used a new optogenetic tool to study how astrocytes, a type of brain cell, affect synaptic plasticity in Huntington's disease. Synaptic plasticity is the brain's ability to change connections between neurons and is known to be altered in this neurodegenerative disorder.
The research team, led by Mercè Masana from the University of Barcelona’s Faculty of Medicine and Health Sciences and the Institute of Neurosciences (UBneuro), published their findings in iScience. The study involved collaboration with several institutions including the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBER Area for Neurodegenerative Diseases (CIBERNED), University of Vic-Central University of Catalonia, Navarrabiomed Proteomics Platform, Aston University in Birmingham, University of Oulu in Finland, Vision Institute in Paris, and University of Bayreuth in Germany.
To investigate how cyclic adenosine monophosphate (cAMP) signaling works in astrocytes during Huntington’s disease, researchers used an optogenetic method that allows light-controlled regulation of cAMP levels. This was tested on healthy mice and a mouse model for Huntington’s disease.
"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," said Mercè Masana.
Results showed that activating cAMP signaling in astrocytes improved synaptic plasticity among neurons. Manipulating this pathway also affected molecular changes at the protein level, increased glutamate release and neuronal potentiation at the cellular level, boosted cortical blood flow within circuits, and improved motor learning behaviorally.
The Huntington’s disease mouse models showed differences such as stronger hemodynamic responses compared to healthy animals. According to the research team: "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."
Masana added: "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."
Regarding future applications for their approach: "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," said Masana.
She concluded that controlling cAMP levels specifically may help develop new treatments not only for Huntington's but also other diseases where increased cAMP benefits neuronal or glial function: "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," she said.
