Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology.

Scientists studied a gene called SLC25A1 in mice to understand autism better. When this gene was overactive in brain cells, the mice showed autism-like behaviors including repetitive jumping. The mice also had brain changes including inflammation, altered brain connections, and disrupted communication between brain cells. This research suggests that problems with how cells process energy and proteins might contribute to autism development.

This study investigated the role of SLC25A1, a mitochondrial citrate transporter, in autism development using genetically modified mice. Researchers created transgenic mice with SLC25A1 overexpression specifically in forebrain neurons. These mice displayed autism-like behaviors including jumping stereotypy, altered brain chemistry with increased citrate and acetyl-CoA levels, disrupted white matter integrity, activated inflammatory brain cells (microglia), and changes in synaptic function and neuron shape. The study builds on previous research linking acetyl-CoA metabolism dysfunction to autism, suggesting that disrupted cellular energy and protein processing pathways may contribute to autism spectrum disorder development.

Findings suggest metabolic pathways involving acetyl-CoA and citrate metabolism may be therapeutic targets for autism. The connection between SLC25A1, ATP citrate lyase, and autism risk supports investigating metabolic interventions. However, human studies are needed to validate these animal model findings.

Animal model findings may not directly translate to humans. Sample sizes not reported. Study focused on overexpression model which may not reflect natural autism development. Abstract lacks detail on control groups and statistical analyses.

N ε-lysine acetylation within the lumen of the endoplasmic reticulum is a recently characterized protein quality control system that positively selects properly folded glycoproteins in the early secretory pathway. Overexpression of the endoplasmic reticulum acetyl-CoA transporter AT-1 in mouse forebrain neurons results in increased dendritic branching, spine formation and an autistic-like phenotype that is attributed to altered glycoprotein flux through the secretory pathway. AT-1 overexpressing neurons maintain the cytosolic pool of acetyl-CoA by upregulation of SLC25A1, the mitochondrial citrate/malate antiporter and ATP citrate lyase, which converts cytosolic citrate into acetyl-CoA. All three genes have been associated with autism spectrum disorder, suggesting that aberrant cytosolic-to-endoplasmic reticulum flux of acetyl-CoA can be a mechanistic driver for the development of autism spectrum disorder.

We therefore generated a SLC25A1 neuron transgenic mouse with overexpression specifically in the forebrain neurons. The mice displayed autistic-like behaviours with a jumping stereotypy. They exhibited increased steady-state levels of citrate and acetyl-CoA, disrupted white matter integrity with activated microglia and altered synaptic plasticity and morphology. Finally, quantitative proteomic and acetyl-proteomic analyses revealed differential adaptations in the hippocampus and cortex.

Overall, our study reinforces the connection between aberrant cytosolic-to-endoplasmic reticulum acetyl-CoA flux and the development of an autistic-like phenotype.