Synaptic adhesion molecule Pcdh-γC5 mediates synaptic dysfunction in Alzheimer’s disease

Abstract

Synaptic dysfunction and neuronal excitatory/inhibitory imbalance have been implicated in Alzheimer’s disease (AD) pathogenesis. Although intensive studies have been focused on the excitatory synaptic system, much less is known concerning the mechanisms mediating inhibitory synaptic dysfunction in AD. We reported previously that protocadherin-κC5 (Pcdh-κC5), a member of clustered Pcdh-κ subfamily of cadherin-type synaptic adhesion proteins, functions to promote GABAergic synaptic transmission. We reveal here that Pcdh-κC5 is enriched in vesicular GABA transporter-positive synaptic puncta and its expression levels are increased in neuronal hyperexcitation conditions, upon β-amyloid (Aβ) treatment, and in amyloid precursor protein (APP)/presenilin-1 (PS1)-transgenic mice of both sexes. This is associated with elevated levels of GABAergic proteins and enhanced synaptic inhibition. Genetic knock-down experimentsshowedthatPcdh-κC5modulatesspontaneoussynapticcurrentsandAβ-inducedsynapticalterationsdirectly. Ourresultssupport a model in which Pcdh-κC5 senses neuronal hyperexcitation to augment GABAergic inhibition. This adaptive mechanism may be dysregulated under chronic excitation conditions such as AD, leading to aberrant Pcdh-κC5 expression and associated synaptic dysfunction.