KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice.

Scientists studied mice with changes to the KMT2E gene, which has been linked to autism in humans. These mice showed autism-like behaviors such as social difficulties and anxiety. Brain scans revealed problems in the amygdala, a brain area important for emotions and social behavior. The amygdala had abnormal development with too many and enlarged brain cells. This research helps explain how certain genetic changes might cause autism symptoms.

This study investigated KMT2E gene mutations in autism spectrum disorders using mouse models. Researchers found that mice with KMT2E haploinsufficiency (reduced gene function) displayed autism-like behaviors including social deficits and increased anxiety. Brain imaging revealed decreased glucose metabolism specifically in the amygdala region. Microscopic analysis showed abnormal amygdala development with increased numbers and sizes of neurons.

The study also found that KMT2E gene expression naturally decreases in human amygdala tissue after birth during development. These findings provide experimental evidence supporting KMT2E as a causative factor in autism development, with amygdala abnormalities as a key underlying mechanism.

Supports KMT2E as autism risk gene and identifies amygdala as key brain region affected. May inform genetic counseling for families with KMT2E mutations. Could guide development of targeted interventions focusing on amygdala function and early developmental periods.

Sample sizes not reported. Single animal model study limits generalizability to human autism. Molecular mechanisms underlying observed phenotypes not fully elucidated. No assessment of intervention strategies or reversibility of observed abnormalities.

Autism spectrum disorders (ASD) are highly heterogeneous neurodevelopmental disorders characterized by impaired social interaction skills. Whole exome sequencing has identified loss-of-function mutations in lysine methyltransferase 2E (KMT2E, also named MLL5) in ASD patients and it is listed as an ASD high-risk gene in humans. However, experimental evidence of KMT2E in association with ASD-like manifestations or neuronal function is still missing. Relying on KMT2Emice, through animal behavior analyses, positron emission tomography (PET) imaging, and neuronal morphological analyses, we explored the role of KMT2E haploinsufficiency in ASD-like symptoms.

Behavioral results revealed that KMT2E haploinsufficiency was sufficient to produce social deficit, accompanied by anxiety in mice. Whole-brainF-FDG-PET analysis identified that relative amygdala glycometabolism was selectively decreased in KMT2Emice compared to wild-type mice. The numbers and soma sizes of amygdala neurons in KMT2Emice were prominently increased. Additionally, KMT2E mRNA levels in human amygdala were significantly decreased after birth during brain development.

Our findings support a causative role of KMT2E in ASD development and suggest that amygdala neuronal development abnormality is likely a major underlying mechanism.