MassIVE MSV000097391

Complete Public PXD062090

Macro_NN_2025_Pro-cognitive reshaping of neuronal dynamics by a human CSF-based factor

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Description

Neuronal connection dysfunction is a convergent cause of cognitive deficits in mental disorders. Cognitive processes are finely regulated at the synaptic level by membrane proteins, some of which are shed and detectable in patients' cerebrospinal fluid (CSF). However, whether these soluble synaptic proteins can harnessed as innovative pro-cognitive factors to treat brain disorders remains unclear. Here, we use quantitative proteomics to identify shed synaptic proteins dysregulated in the CSF of subjects with schizophrenia (SCZ), a mental disorder characterized by cognitive and synaptic dysfunction. The level of a yet uncharacterized soluble form of the voltage-gated calcium channel auxiliary subunit, alpha2delta-1, is robustly reduced in SCZ CSF. Remarkably, soluble alpha2delta-1 is convergently downregulated across several brain disorder CSF proteomes. We show that the brain releases soluble alpha2delta-1 in an activity-dependent manner, which can reorganize neuronal network dynamics by binding to synaptic targets and promoting inhibitory neuron plasticity. A single brain injection of a synthetic soluble alpha2delta-1 improved interneuron and cognitive deficits in a mutant mouse model of SCZ and cortical dysfunction. These findings underscore the potential of shed synaptic proteins as novel therapeutic agents capable of enhancing brain function in diverse brain disorders characterized by cognitive impairment. [doi:10.25345/C5X05XR19] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Schizophrenia ; cerebrospinal fluid ; Cacna2d1 ; cognition ; synapses ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Peter Penzes, Northwestern University, Feinberg School of Medicine, United States
Submitting User: jeffsavas
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