In the present work, we have showed that (i) BSCB structural and functional disruption is detected in four ALS mouse lines with unrelated mutations and different degrees of MN loss; (ii) the disruption of the BSCB takes place before any MN loss (in at least two lines), and it is restored by enhancing MN excitability; and (iii) the activation of Gi signaling in astrocytes reverts the disruption of the BSCB by increasing Wnt5a/Wnt7a expression but without impacting the burden of disease markers in MN and independently of MN firing. Here, WNT5A is linked to amyotrophic lateral sclerosis.