Loss of Necdin causes social deficit and aberrant synaptic function through destabilization of SynGAP

Abstract

The Ras GTPase-activating protein SynGAP interacts with PSD95 to regulate synaptic morphology and function at the postsynaptic density in neurons. Haploinsufficiency of SYNGAP1 has been linked to autism spectrum disorders (ASD) and intellectual disability (ID). While transcriptional and translational regulation of SYNGAP1 has been extensively explored, the mechanisms governing its protein homeostasis remain largely elusive. In this study, we discovered that Necdin, a protein linked to Prader-Willi syndrome (PWS), interacts with SynGAP and regulates its stability through the SGT1-HSP90 chaperone machinery; notably, depletion of Necdin results in decreased SynGAP protein levels in mice. Loss of Necdin lead to impaired sociability, accompanied by an increased number of dendritic spines and a higher proportion of mature spines in pyramidal neurons of the medial prefrontal cortex (mPFC) in mice. Electrophysiological recordings revealed elevated frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) and reduced amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in these neurons. Targeted viral overexpression of Syngap1 in the mPFC of Necdin-deficient mice rescued the deficits in sociability, synaptic function, and dendritic spine morphology. Collectively, our findings reveal Necdin as a key regulator of SynGAP protein homeostasis and highlight the contribution of post-translational regulation in the pathogenesis of ASD.