What closes the critical period for circuit plasticity?

In Chapter 7 of Principles of Neurobiology, we learned about (1) How individual neurons differentiate and connect with their partners and (2) How groups of neurons coordinate their wiring to form a functional circuit. Neural development is a sequential differentiation process: pattern the dividing progenitors, neuronal birth, neuronal migration, axon pathfinding, dendrite morphogenesis, synapse formation and modification of synaptic connections. In particular, we learned that neural activity refines neural targeting and synaptogenesis (sections 7.13, 7.19 and 7.31). This phenomenon is discussed in more details in visual system in Chapter 5 (sections 5.7-5.14). In the visual system Hubel and Wiesel performed a series of time-course experiments and discovered a window named critical period for neural activity to affect wiring. While synaptic plasticity occurs widely in the adult brain, substantial activity-dependent remodeling happened during early development. However, it is not known why there is such a critical period and how it is regulated. Two recent papers provided independent evidences showing that astrocytes close the critical period in Drosophila motor circuits and mouse visual circuit.

To study the mechanisms that ensure timely critical period closure, Ackerman et al. first defined a critical period in a new system, the developing Drosophila motor circuit, as most studies in the field focused on sensory circuits before. During the critical period, the last hour of embryogenesis (stage 17), activity regulates dendrite length, complexity and connectivity of motor neurons. They showed that silencing motor neurons during critical period increased dendritic volume at 0 h after larval hatching (ALH), whereas silencing for 1 h at later stages showed progressively less of an effect, with no remodeling occurring at 8 h ALH or beyond. The correlation between the critical period and the time when astrocyte invade neuropil led the authors to propose a function of astrocyte in closing the critical period. Indeed, they found that astrocyte ablation prolonged the critical period. To understand how astrocyte regulate critical period closure, the authors performed a genetic screen to identify astrocyte-motor neuron signaling pathways that close the critical period, including Neuroligin-Neurexin signaling. Specifically they showed that dendritic microtubules are destabilized upon decreased signaling, resulting in more dendrite dynamicity and impaired locomotor behavior (Ackerman et al., 2021).

A second paper (Ribot et al. 2021) showed a similar function of astrocyte in critical period closure in the mouse visual system. Here, the authors performed an interesting experiment in which they injected GFP+ immature astrocytes that were cultured in vitro for 10 days into the primary visual cortex (V1) of adult mice (P100), in which the critical period is closed. Through testing the ocular dominance (OD) plasticity they found that mice engrafted with immature astrocytes displayed a high level of plasticity. This indicates that immature astrocytes reopen OD plasticity in adult mice. They proposed that some signal from the mature astrocytes close the critical period. To find out this signal, they compared expression profiles from immature and mature astrocytes and uncovered unconventional astrocyte connexin signaling hinders expression of extracellular matrix–degrading enzyme matrix metalloproteinase 9 (MMP9) through the activation of small GTPase RhoA.

Together, these two papers support for a function of astrocytes in closing critical periods. Each paper revealed some mechanisms through which astrocytes regulate critical period closure. It is not clear whether astrocytes regulate this process through several parallel downstream signaling pathways but in a similar manner between species (tissues), or the mechanisms vary in different contexts. These findings are important for future study how the critical period is regulated in normal and pathogenic conditions during development.

Reference

Ackerman, S. D., Perez-Catalan, N. A., Freeman, M. R. & Doe, C. Q. (2021) Astrocytes close a motor circuit critical period. Nature. 2021 Apr;592(7854):414-420.Link

Ribot, J., Breton, R., Calvo, C. F., Moulard, J., Ezan P., Zapata, J., Samama, K.,…& Rouach N. (2021) Astrocytes close the mouse critical period for visual plasticity. Science. 2021 Jul 2;373(6550):77-81 Link