Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• SHANK3 gene mutations are linked to Phelan-McDermid syndrome and autism spectrum disorder (ASD).
• SHANK3 protein is crucial for excitatory synapse function.
• Previous studies noted behavioral impairments and altered neuron morphology in Shank3-deficient animal models.

Purpose of the Study:

• To investigate the impact of SHANK3 deficiency on neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC) of a rat model.
• To explore potential alterations associated with attentional deficits observed in Shank3-deficient animals.

Main Methods:

• Compared mPFC layer III neuron morphology and spine density in Shank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats.
• Utilized electron microscopy to analyze synapse density, postsynaptic density (PSD) length and area, and spine head diameter (HD).

Main Results:

• Dendritic morphology was similar across genotypes.
• Shank3-Het rats showed larger spine head volumes and significantly increased spine HD and PSD area compared to WT rats.
• Synapse density and PSD length were comparable among all groups; Shank3-KO rats did not show the same increases as Shank3-Het rats.

Conclusions:

• Heterozygous loss of SHANK3 in rats is associated with altered synaptic ultrastructure in the mPFC.
• These findings support a significant role for SHANK3 protein dysfunction in the pathophysiology of ASD and Phelan-McDermid syndrome.