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

Scientists studied a protein called Necdin in mice and found it helps control social behavior. When mice lacked this protein, they had trouble with social interactions and showed brain changes similar to those seen in autism. The researchers discovered that Necdin works by protecting another important brain protein called SynGAP. When they restored SynGAP levels in the mice's brains, the social problems improved, suggesting this could be a potential treatment approach.

This preclinical study investigated the role of Necdin protein in autism-related behaviors and brain function. Researchers found that Necdin regulates the stability of SynGAP, a protein previously linked to autism spectrum disorders. When Necdin was depleted in mice, it led to decreased SynGAP levels, social deficits, and abnormal brain connectivity patterns. The study showed increased dendritic spines and altered electrical activity in brain cells responsible for social behavior.

Importantly, restoring SynGAP levels through viral gene therapy rescued the social deficits and normalized brain function, suggesting a potential therapeutic target for autism-related social challenges.

Findings suggest SynGAP pathway as potential therapeutic target for social deficits in autism. However, translation to human applications requires extensive additional research. Current findings are preliminary and limited to preclinical models.

Study conducted only in mouse models with findings requiring validation in human studies. Sample sizes not reported. Long-term safety and efficacy of viral gene therapy approach unknown. Unclear generalizability to human autism spectrum disorders.

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.