Researchers from The John Curtin School of Medical Research (JCSMR) have uncovered aspects of the cellular mechanisms underlying the development of autism spectrum disorder (ASD).
ASD is a diverse group of neurodevelopmental disorders characterised by an imbalance between the excitatory and inhibitory neurotransmission in the brain.
The interneurons, a critical type of neuron that regulates the flow of information in the nervous system, seem to be at the centre of this imbalance.
Previous studies have associated loss-of-function mutations in the Cntnap2 gene with diagnosed ASD and epilepsy in humans.
Dr Dehorter and her team used a cutting-edge sequencing tool called Stereo-seq to map the gene expression of Cntnap2 onto the brain at a sub-cellular level.
"It's a highly powerful technique for highlighting the spatial distribution of different neuronal subtypes in the brain," said Dr Dehorter, "Previously, we could only sequence the cells without knowing their exact locations within the brain."
Cntnap2 mRNA expression in the adult mouse brain slice. Image: Ahmed NY et al. Front. Cell Dev. Biol. (2023)
With Stereo-seq, the researchers found that Cntnap2 is abundant in a specific subset of interneurons in both developing and adult brains.
How are these interneurons affected in the absence of Cntnap2?
The team investigated the changes in the interneurons in the ASD mouse model where the Cntnap2 gene is inactivated (knocked out).
"We found that the developmental trajectory of this specific subtype of interneuron was perturbed from embryonic stages, with deficits lasting after birth." said Dr Dehorter, "The absence of Cntnap2 impacted the function of these cells and the whole neuronal network."
Interneurons in the Cntnap2 knockout mouse model showed alterations, compared to normal mice, in proliferation, morphology, and electrical properties in the developing striatum, a brain region crucial for learning and decision-making.
"Interneurons essentially keep all the excitatory neurons that send commands throughout the brain in check and make sure they don't overload as seen in epilepsy, which is frequently reported in people with ASD," explained Neuroscience PhD student Noorya Ahmed, the lead author of this study.
The observed early alterations in interneurons could result in dysfunction in the striatum and likely contribute to the pathogenesis of ASD.
The findings and implications have been published in Frontiers in Cell and Developmental Biology.
With the neural differences delineated in the ASD mouse model, said Noorya, the study lays the foundation for future studies aimed at restoring the brain's excitation-inhibition balance in autism.
"Future therapeutic approaches targeting interneurons may yield effective in halting the most deleterious impact of the progress of ASD," said Dr Dehorter.