Schizophrenia-associated glycoprotein Adamtsl3 regulates perineuronal net formation, maintenance, and adult cortical plasticity

Teresa M L Cramer; Saad B Hannan; Lucie Petre; Mark F Bear; Takao K Hensch; Shiva K Tyagarajan

doi:10.1038/s41380-026-03672-7

Schizophrenia-associated glycoprotein Adamtsl3 regulates perineuronal net formation, maintenance, and adult cortical plasticity

Mol Psychiatry. 2026 Jun 11. doi: 10.1038/s41380-026-03672-7. Online ahead of print.

Authors

Teresa M L Cramer^{1

2

3}, Saad B Hannan², Lucie Petre¹, Mark F Bear³, Takao K Hensch^{2

4

5}, Shiva K Tyagarajan^{6

7}

Affiliations

¹ University of Zurich, Institute of Pharmacology and Toxicology, Winterthurerstrasse 190, Zürich, 8057, Switzerland.
² Department of Molecular Cellular Biology, Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, MA, 02138, USA.
³ Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁵ International Research Center for Neurointelligence, University of Tokyo Institutes for Advanced Study, Bunkyo-ku, Tokyo, 113, Japan.
⁶ University of Zurich, Institute of Pharmacology and Toxicology, Winterthurerstrasse 190, Zürich, 8057, Switzerland. shiva.tyagarajan@uc.pt.
⁷ University of Coimbra, Dept. of Life Sciences, Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, Rua Larga - POLO I, Coimbra, 3004-504, Portugal. shiva.tyagarajan@uc.pt.

PMID: 42277231
DOI: 10.1038/s41380-026-03672-7

Abstract

Perineuronal nets (PNNs) regulate the maturation of parvalbumin-positive (PV+) interneurons during postnatal critical periods and continue to support their function thereafter. Their disruption is implicated in neuropsychiatric disorders such as schizophrenia, yet key endogenous PNN regulators remain unknown. Here, we identify the schizophrenia-associated glycoprotein Adamtsl3 as a PV+ cell-autonomous regulator of PNN integrity. Using mouse genetics, morphological and biochemical analyses, we demonstrate that Adamtsl3 deletion, both in early postnatal and adult stages, results in PNN deficits. Mechanistically, Adamtsl3 modulates matrix metalloprotease-9 (MMP9) activity, and Adamtsl3 deletion results in elevated MMP9 levels, PNN reduction, decreased Otx2 uptake, and heightened oxidative stress in PV+ cells. MMP9 hyperactivity and PNN reduction can be rescued by pharmacological inhibition of MMP9. Deletion of Adamtsl3 in PV+ interneurons revealed its cell-autonomous function in modulating PNN integrity. Notably, conditional Adamtsl3 deletion in adult PV+ cells reactivated juvenile-like ocular dominance plasticity. These results position Adamtsl3 as a persistent, PV+ specific PNN regulator with direct implications for the pathophysiology of schizophrenia.

Abstract

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