What does the latest research tell us about the cause of autism?

Recent research on autism spectrum disorder (ASD) has deepened our understanding of its causes, pointing to a combination of genetic, molecular, and neurodevelopmental factors:

1. Genetic Mechanisms: Studies, including one from UCLA, have linked autism to specific genetic changes that affect brain development and activity. Using advanced single-cell assays, researchers identified alterations in neurons and glial cells that connect brain regions. They highlighted transcription factor networks that regulate gene expression, providing insight into how genetic predisposition can lead to observable brain changes in ASD​.
2. Neurotransmitter Switching: Research at UC San Diego found that early developmental changes in neurotransmitters, such as the replacement of GABA with glutamate in certain neurons, can disrupt brain wiring. This abnormal electrical activity during early development could lead to the behavioral and social challenges seen in autism, suggesting a potential primary cause at the molecular level​. [1]
   • This study (Embryonic exposure to environmental factors drives transmitter switching in the neonatal mouse cortex causing autistic-like adult behavior)examines how prenatal exposure to valproic acid (VPA) or a maternal immune challenge (Poly I:C, mimicking viral infection) alters brain development and behavior in mice. These environmental factors are associated with an increased risk of autism spectrum disorder (ASD) and schizophrenia in human offspring.
   • Key Findings:
   • Experimental Setup:
     • Pregnant mice were injected with saline, VPA, or Poly I:C on embryonic day 12.5 (E12.5), a critical period for brain development.
     • Researchers analyzed brain changes in mouse pups at postnatal day 10 (P10), before secondary consequences of brain development emerge.
   • Brain Changes:
     • In the medial prefrontal cortex (mPFC), VPA and Poly I:C exposure led to a shift in neurotransmitter identity:
       • A decrease in neurons producing GABA (an inhibitory neurotransmitter).
       • An increase in neurons producing glutamate (an excitatory neurotransmitter).
     • These changes did not stem from neuron loss, apoptosis, or differences in neuron precursor populations, indicating a direct switch in neurotransmitter type.
   • Behavioral Effects:
     • At adulthood (P90), mice exposed to VPA or Poly I:C exhibited autism-like behaviors:
       • Increased repetitive behaviors (e.g., burying more marbles, excessive grooming).
       • Reduced interest in social interaction, especially in male mice.
     • These behavioral changes parallel patterns observed in humans with ASD.
   • Reversibility of Brain Changes:
     • The neurotransmitter identity shift (from GABA to glutamate) was present during early development (P10 to P21) but reverted to normal by P30.
     • This suggests a transient disruption during a critical period of brain development.
   • Specific Neurons Affected:
     • The change primarily affected neurons expressing parvalbumin (PV) and cholecystokinin (CCK), subtypes of GABAergic neurons important for brain signaling balance.
   • Implications:
   • This study provides insight into how environmental exposures during pregnancy, like medications (e.g., VPA) or viral infections, can disrupt brain signaling in offspring.
   • The findings support the idea that early disruptions in neurotransmitter systems contribute to autism-like behaviors.
   • Understanding these mechanisms could guide therapeutic strategies or preventive measures for ASD and related disorders.
   • Would you like further explanation of any part of the study?
3. Environmental Interactions: While not discussed in these studies, previous research also emphasizes how genetic susceptibility interacts with environmental factors, like prenatal exposures, to influence the likelihood of developing ASD.

These findings underscore the complexity of autism’s origins, combining genetic risk factors with specific cellular and molecular mechanisms in the brain. The ultimate goal is to use this understanding to develop targeted interventions and therapies.

1. https://www.pnas.org/doi/10.1073/pnas.2406928121