Brain plasticity has been postulated to be mainly mediated by neurons. Now, investigators led by Nathalie Rouach at the Center for Interdisciplinary Research in Biology, College De France have demonstrated the role of astrocytes in mediating brain plasticity.
They found that during development of the mammalian brain's primary visual cortex, astrocytes regulated the critical period via a signaling pathway controlled by the cell junction protein connexin 30.
The team reported its results in the July 1, 2021, online issue of Science. Rouach is a director of research at College de France. Her group studies the role of astrocytes in behavioral states and cognitive functions.
Brain plasticity is a transient period after birth in which the brain remodels the "wiring" of the neurons according to the external environment. Plasticity is greatest during specific windows of time during brain development post birth. During these critical periods, formation of neural networks takes place. Termination of these periods of intense plasticity is associated with settling of neuronal circuits, allowing for efficient information processing and cognitive development. Failure to end critical periods thus results in neurodevelopmental disorders.
Astrocytes are key active elements of the central nervous system that not only provide neurons with metabolic and structural support, but also regulate neurogenesis and brain wiring. The researchers found that that transplanting immature astrocytes into the brains of adult mice reintroduced a period of major plasticity. In the study, Rouach and her team cultured immature astrocytes from the visual cortex of young mice (1-3 days old) and transplanted these into the primary visual cortex of adult mice, following which the activity of the visual cortex was evaluated.
"The mice transplanted with the immature astrocytes showed increased ocular dominance (OD) plasticity that occurred after visual stimulation of one eye as compared to non-grafted control mice," Rouach told BioWorld Science. Rouach believes that these findings emphasize the active and direct role of astrocytes in information processing.
In order to identify how immature astrocytes allow OD plasticity, Rouach and her team studied the molecular determinants of astrocyte maturation. They found that more than 200 genes were differentially expressed in immature and mature astrocytes. Among those genes was the gene encoding connexin 30 (Cx30).
Cx30 is a subunit of a gap junction channel, a specialized intercellular connection between cells. Rouach said that "we observed that the expression of Cx30 in the primary visual cortex was the greatest when the critical period for ocular dominance plasticity ended. We, therefore decided to assess plasticity in a mouse model genetically engineered to lack Cx30. Although OD plasticity peaked at about postnatal day 28 in wild-type mice, it continued to increase in mice lacking Cx30 until postnatal day 50, indicating impairment in the closure of the critical period." Rouach's team also found that the engrafted animals had smaller perineuronal nets. Perineuronal nets are a highly organized form of extracellular matrix that contains chondroitin sulfate proteoglycans and contribute to the closure of ocular dominance plasticity.
According to Rouach, these results indicate that astrocytes regulate the critical period by promoting the maturation of inhibitory circuits through signaling pathways that involve Cx30. Cx30 was found to inhibit expression of MMP-9 (matrix metalloproteinase-9) via the RhoA-ROCK (Rho-associated coiled-coil-containing protein kinase 2) pathway, thereby hindering maturation of local inhibition. Immature astrocytes present with low levels of CX30, which activates the RhoA-ROCK2 pathway, dissolves perineuronal nets surrounding inhibitory neurons leading to increased neural plasticity of the primary visual cortex.
According to Rouach, "The regulation of MMP-9 levels that we describe in this study occurs via an unconventional signaling pathway through Cx30 and represents a novel astroglial pathway regulating wiring of brain circuits."
Because extended critical periods are associated with neurodevelopmental defects resulting in sensorimotor or psychiatric disorders, these findings can "provide a new target for the development of strategies aiming at re-inducing a period of enhanced plasticity in adults and favor rehabilitation after brain damage or developmental malfunction," added Rouach.
Rouach wants to explore whether there are other signaling pathways in which astrocytes influence the use-dependent plasticity of neural circuits during development.
Her group's future work will focus on trying to understand the diverse underlying mechanisms of synaptic circuit control by astrocytes in both animal and human tissues.