Delayed astrocyte development impairs Sema6a-Plxna2/4-mediated astrocyte-neuron crosstalk and causes depressive-like behavior

Neural functions and circuit formation rely on intricate crosstalk among various cell types during critical periods. Disruptions or delays in this crosstalk between neurons and astrocytes lead to abnormal neural functions and neurodevelopmental disorders. However, the lack of robust mouse models to study the crosstalk between astrocytes and neurons thus renders unclear the implications of impeding such interactions. In this study, we demonstrate that Egfr knockout during the critical period of neuronal maturation results in a transient absence of astrocytes, with recovery observed in adult mice. This model thus provides a unique opportunity to investigate the effects of impaired astrocyte-neuron communication during development. Mechanically, we show that loss of Egfr disrupts the Egfr-pERK-Epb41l2 signaling axis, which in turn prevents glial progenitor cells from migrating outward. More importantly, Egfr deficiency during the critical period compromises astrocyte-neuron communication via the Sema6a-Plxna2/4 ligand-receptor pair. This impaired intercellular crosstalk reduces neuronal dendritic complexity and excitability, ultimately culminating in depressive-like behaviors in adult mice.