POSH regulates assembly of the NMDAR/PSD-95/Shank complex and synaptic function

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in Shank/ProSAP genes are linked to autism spectrum disorders (ASDs) and intellectual disability.
• Dysfunction of N-methyl-D-aspartate glutamate receptors (NMDARs) is implicated in autism-like behaviors.
• The precise molecular mechanisms of Shank-mediated NMDAR modulation remain unclear.

Purpose of the Study:

• To investigate the role of the scaffold protein plenty of SH3s (POSH) in synaptic function and autism-like behaviors.
• To elucidate the molecular interactions between POSH, PSD-95, and SHANK proteins at excitatory synapses.

Main Methods:

• Utilized conditional knockout (cKO) mouse models for POSH.
• Examined synaptic clustering of NMDAR/PSD-95/SHANK complexes in hippocampal neurons.
• Assessed dendritic spine development and glutamatergic transmission.
• Behavioral analyses of POSH cKO mice for social interaction, communication, repetitive behaviors, learning, and memory.

Main Results:

• POSH directly interacts with PSD-95 and SHANK2/3 at excitatory synapses.
• POSH cKO mice exhibit disrupted synaptic clustering of the NMDAR/PSD-95/SHANK complex.
• Abnormal dendritic spine development and impaired glutamatergic transmission were observed in POSH cKO mice.
• POSH cKO mice displayed significant autism-like behaviors, including social deficits and cognitive impairments.

Conclusions:

• POSH acts as a critical scaffold protein at the postsynaptic density (PSD), co-clustering with PSD-95 and SHANK2/3.
• POSH plays a vital role in NMDAR signaling complex function, synaptic development, and overall brain function.
• These findings highlight POSH as a potential therapeutic target for ASDs.