Recent research from the Salk Institute has unveiled that the astrocyte-secreted protein CCN1 plays a pivotal role in stabilizing neural circuits in the adult brain. Published in the journal Nature, the study highlights how this protein could serve as a new therapeutic target for various neurological disorders, including Alzheimer’s disease, depression, and post-traumatic stress disorder (PTSD).
Traditionally, astrocytes were viewed merely as support cells in the brain. However, this study emphasizes their significant contribution to the stability and maintenance of sensory circuits during adulthood. According to the study’s corresponding author, Nicola Allen, PhD, professor and co-director of the NOMIS Foundation-funded Neuroimmunology Initiative at Salk, “This study establishes the crucial role of astrocytes in actively stabilizing the connectivity of neuronal circuits.”
The research reveals that the stability of sensory circuits in the adult brain is actively preserved by astrocytes, a discovery that could inform the development of new treatments for brain injuries and strokes, conditions associated with the upregulation of CCN1.
Understanding Neural Plasticity and Circuit Stability
In mammals, sensory circuits exhibit higher plasticity during youth, a crucial period for circuit refinement. This plasticity diminishes as the brain matures, leading to increased stability. While maintaining stability is essential for functional connectivity, the study indicates that the potential for circuit plasticity can be reactivated through specific interventions, such as enzymatic digestion of the extracellular matrix or the transplantation of juvenile astrocytes or inhibitory neurons.
To explore the role of astrocytes in this process, researchers focused on the mouse visual cortex. By employing a combination of transcriptomic analysis, ex vivo electrophysiology, and in vivo imaging, the team found that heightened expression of CCN1 resulted in greater cellular maturation in both inhibitory neurons and oligodendrocytes. This maturation dampened the circuits’ neuroplasticity. In contrast, deleting CCN1 in astrocytes led to destabilization of binocular circuits and decreased myelination.
Implications for Future Therapeutics
The findings suggest that manipulating CCN1 levels may provide a means to control neuroplasticity, potentially aiding the recovery or reconstruction of lost circuits following injury or trauma. CCN1 is known to interact with various extracellular components across multiple cell types, including excitatory and inhibitory neurons, oligodendrocytes, and microglia. By binding to integrin proteins on cell surfaces, CCN1 coordinates the maturation of these cells, which in turn reduces the plasticity of the adult brain.
First author Laura Sancho, PhD, a postdoctoral researcher in Allen’s lab, stated, “Maintaining stable circuits is important for proper brain function, but the consequence is that neural plasticity and remodeling are repressed in the adult brain. We wanted to find out if and how astrocytes participate in this critical maintenance, and we found they are in fact essential.”
The study not only sheds light on the intricate workings of brain circuitry but also offers hope for developing new strategies to treat debilitating neurological conditions. With further research, CCN1 could emerge as a crucial target in the quest for effective therapies that enhance neuroplasticity and support brain health throughout adulthood.
