Brain region and gene dosage-differential transcriptomic changes in Shank2-mutant mice

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Shank2 protein is crucial for excitatory synapses and linked to neurodevelopmental disorders like ASD.
• Shank2 mutations in mice cause behavioral and synaptic deficits, but regional transcriptomic effects are unclear.

Purpose of the Study:

• To investigate how brain region and Shank2 gene dosage affect transcriptomic changes in Shank2-mutant mice.
• To identify specific transcriptomic patterns in different brain regions and their relation to ASD-risk genes.

Main Methods:

• RNA-sequencing (RNA-Seq) was used for transcriptomic analysis.
• Adult Shank2 heterozygous (HT) and homozygous (HM) mutant mice lacking exons 6-7 were studied.
• Prefrontal cortex, hippocampus, and striatum were analyzed.

Main Results:

• Distinct transcriptomic patterns related to synapse, ribosome, mitochondria, spliceosome, and ECM were observed across brain regions.
• Differential expression of ASD-related and ASD-risk genes varied by brain region.
• The prefrontal cortex showed the most pronounced effects, with HT mice exhibiting increased synaptic gene expression and HM mice showing decreased synaptic gene expression.

Conclusions:

• Transcriptomic alterations in Shank2-mutant mice are specific to brain region and gene dosage.
• Findings highlight the complex genetic architecture underlying neurodevelopmental disorders associated with Shank2 mutations.