Description:

Marc Dos Santos, PhD: Work-in-Progress Seminar Abstract

Dysfunction of neuronal connectivity is a convergent cause of cognitive deficits in several mental disorders. Cognitive processes are finely regulated at the synapse by membrane proteins, some of which are shed and detectable in patients’ cerebrospinal fluid (CSF). This work in progress aims to investigate whether these soluble synaptic proteins can be harnessed as novel neuronal network modulators to treat psychiatric disorders.

First, we used quantitative proteomics to identify shed, soluble, synaptic proteins dysregulated in the CSF of subjects with schizophrenia (SCZ), a mental disorder characterized by cognitive and synaptic dysfunction. We found reduced protein levels of a yet uncharacterized soluble form of the voltage-gated calcium channel auxiliary subunit, Alpha2/Delta-1 (encoded by the CACNA2D1 gene) in the CSF in SCZ. Remarkably, protein levels of soluble Alpha2/Delta-1 are convergently downregulated across several brain disorder CSF proteomes, including Alzheimer’s disease.

We show that the brain release of soluble Alpha2/Delta-1 is activity-dependent, which can reorganize local neuronal network dynamics by interacting with synaptic complexes and promote inhibitory neuron plasticity. A single brain injection of a synthetic soluble Alpha2/Delta-1 improved synaptic plasticity in PV-interneuron and social/cognitive deficits in a mutant mouse model relevant for SCZ and presenting cortical dysfunction. These findings underscore the potential of shed CSF synaptic proteins as novel therapeutic agents capable of enhancing brain function in diverse brain disorders characterized by cognitive impairment.