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

## TL;DR

Neuronal activity causes PCDH9 to be cut and move to the nucleus, helping to reshape brain connections and function.

## Contribution

A novel activity-dependent signaling pathway for Pcdh9 is identified, linking synaptic activity to structural and functional changes.

## Key findings

- Neuronal activity triggers MMP-dependent cleavage of PCDH9, producing a C-terminal fragment.
- PCDH9 CTF promotes dendritic growth and increases spine density while enhancing excitatory synaptic transmission.
- PCDH9 CTF acts as a signaling molecule connecting synaptic activity to structural and functional remodeling.

## Abstract

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.