Connection and communication represent two crucial concepts in the massive and complex network that is the mammalian brain; therefore, the disruption of neural connections during early development may promote the onset of neurodevelopmental disorders. Previous studies have linked the histone methyltransferase SETD5 with autism spectrum disorders (ASD), which inspired researchers from the lab of Alysson Muotri (University of California, San Diego, USA) to investigate the functional implications of SETD5 haploinsufficiency. Interestingly, their new research employing Setd5+/− mice and cultured embryonic neurons supports a model in which the loss of histone methyltransferase activity “disconnects” the developing brain and prompts the development of autism-like behavioral symptoms.
So disconnect from those other papers and read the highlights of this new study from Moore and colleagues:
- Setd5+/− cerebral cortex neurons display significantly reduced synaptic density and
neuritic outgrowth, resulting in decreased network activity and synchronized
activity (as measured by in vitro electrophysiological
approaches)
- Single-cell RNA-sequencing of sorted brain cells revealed that a specific subpopulation of fetal Setd5+/− neurons expressed altered levels of critical neurodevelopment-related genes
- This altered gene expression patterns may contribute downstream to the generation of cortical networks with significantly lower overall connectivity that could contribute to behavioral abnormalities
- Behavioral assessments of Setd5+/− adult mice highlighted the appearance of several autism-like behaviors, such as hyperactivity, cognitive deficit, and altered social interaction
- Neuroanatomical-neurobehavioral
correlation analysis in Setd5+/− adult brains (via magnetic
resonance imaging to detect region-specific differences in brain volume and
connectivity) uncovered notable alterations when compared to wild-type mice
- Autism-relevant brain regions, such as the secondary auditory cortex, dorsolateral orbital cortex, and frontal association cortex, exhibit significant differences
- The study also revealed an additional deficit of deep-layer cortical neurons in the developing brain
- Importantly for disease modeling, the deficiencies detected in haploinsufficient mice correlate to those observed in human ASD patients harboring SETD5 loss of function mutations
“We only had clinical and genetic evidence that the gene (SETD5) was related to autism. Now, with this mouse model, we have direct causal evidence linking this gene with neuronal molecular and cellular alterations leading to ASD-like behavior,” said senior author Alysson Muotri. “This animal model might be useful when testing potential therapeutic alternatives for this subgroup of ASD in people. Our plans also include the development of human brain organoids derived from reprogrammed cells from ASD individuals.”
Don’t miss any of the crucial connections from this great new study; discover them all at Translational Psychiatry, January 2019.