Suppression of follistatin by spontaneous seizures dysregulates neurogenesis in a model of Alzheimer’s disease neuropathology

Adult hippocampal neurogenesis is perturbed in neurological disorders accompanied by seizures, including Alzheimer’s disease (AD). The molecular mechanisms by which seizures disrupt neurogenesis are unclear. Here, we report that follistatin (FST), an antagonist of TGFβ ligands, plays a pivotal role in seizure-induced dysregulation of neurogenesis.

We find that FST expression is reduced in the dentate gyrus of a mouse model of AD neuropathology that exhibits infrequent spontaneous seizures similar to those in individuals with AD. Treatment with an antiseizure drug improves FST expression in AD mice, whereas a seizure-inducing agent suppresses FST expression in wild-type mice. We identify c-Fos, whose expression is suppressed by the seizure-induced transcription factor ∆FosB, as a transcriptional activator of Fst.

Lastly, ablation of Fst dysregulates neurogenesis dynamics in wild-type mice, whereas FST treatment normalizes dynamics in AD mice. These findings reveal a previously unidentified activity-dependent mechanism in which the expression of FST controls neurogenesis dynamics. Matzuk for the generous gift of Fstflox/flox mice, Dr.

Mauro Costa-Mattioli for the generous gift of CamKIIα-Cre mice, and Dr. Matthew Torre for guidance in the immunostaining of human brain tissues. This work was supported by NIH grants NS086965 and NS085171 (J.C.).

Research reported in this publication was also supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number P50HD103555 for use of the Neurovisualization Core and the Optogenetics and Viral Vectors Core facilities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Figures 1a, 5a, and 6a were partially created in BioRender.

Campbell, J. (2026) https://BioRender.com/tu7rp3. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA Yoshitaka Furuta, Jessica Wang, Chia-Hsuan Fu, Manuel Silva-Pérez, Mawada S. Al Faisal, Minjung Lee, Wangjie Yu & Jeannie Chin Department of Pathology, University of Southern California, Los Angeles, CA, USA Department of Physiology and Neuroscience, University of Southern California, San Diego, CA, USA The authors declare no competing interests.