Neuronal activity drives PCDH9 cleavage and nuclear translocation to coordinate structural and functional remodelling

Federico Miozzo^1,2*Annalaura Zambrano Avendano²Maria Giuseppa Caso²Shinji Hirano³Edoardo Moretto²Luca Murru²Maria Passafaro^2*

• ¹Instituto de Neurociencias (UMH-CSIC), Alicante, Spain
• ²Institute of Neuroscience (CNR), Milano, Italy
• ³Laboratory of Cell Biology, Faculty of Medicine, Kansai Medical University, Hikarata City, Japan

Protocadherins are key regulators of neurodevelopment and synaptic function, acting not only as adhesion molecules but also as synaptic hubs for intracellular signaling. Here, we uncover a novel activity-dependent signaling pathway for Pcdh9, a protocadherin linked to Autism Spectrum Disorder and Major Depressive Disorder. By combining biochemical and immunohistochemistry approaches on neuronal cultures, we show that neuronal activity triggers Matrix Metalloproteases (MMP)-dependent cleavage of PCDH9, generating a C-terminal fragment (CTF) that translocates to the nucleus. PCDH9 CTF overexpression promotes dendritic growth, increases spine density, and concomitantly strengthens excitatory synaptic transmission. These findings identify PCDH9 CTF as a novel activity-dependent signaling molecule that links synaptic activity to structural remodeling and functional modulation, suggesting a new mechanism by which synaptic activity shapes neuronal properties.