Autism Driven by Effects of Early-Life Seizures, Study Says

Frances E. Jensen, MD

A new study has found associations between early-life seizures and neurodevelopmental delay in children with autism and other intellectual disabilities. The findings suggest current therapies that silence certain key synapses may allow children’s brains to develop normally — even after episodic seizures.

Researchers from Penn Medicine have uncovered a causality between epilepsy and early-life seizures to intellectual disorders that goes beyond the significant rate of correlation. Up to 40% of children with autism also suffer from epilepsy, and another 35% of children with infantile spasm develop long-term intellectual disabilities. Though previous studies have associated multiple autism-linked genes with epilepsy, the 2 conditions may also be co-acquired through early-life brain injury or seizures.

“Children with intellectual disorders related to early-life epilepsy and autism often show impaired acoustic temporal and phonological processing that may contribute to later language deficits,” researchers wrote. “Such auditory encoding abnormalities in children with autism are linked to perturbed development of auditory cortex.”

This impaired processing is linked to period of time in brain development where synapses associated with learning and language skills are activated.

Juvenile mouse models induced with seizures were observed for the study. Mice with autism similarly show impaired auditory cortical development to that observed in humans, who are more likely to show impaired acoustic temporal and phonological processing — and eventually, language deficits — when they suffer from early-life epilepsy.

Researchers found in preclinical studies that mice models induced with seizures that “silent” thalamocortical synapses in the auditory cortex containing only NMDA receptors switched to “unsilent” with both NMDA and AMPA receptors, meaning the brain prematurely activated pathways and receptors associated with sensory information and memory. Days later, a disruption in the auditory synapses was found in the models.

Honing in on this space of time — and understanding the precise changes to synapses following seizures — could give clinicians a chance to properly treat to prevent this “unsilencing,” senior author Frances E. Jensen, MD, chair of the Department of Neurology at the Perelman School of Medicine at Penn, said in a statement.

“The timing is important: We need to stop it right after the seizures and before a critical period of development in a child’s life so the brain can develop without any problems that may lead to future impairments,” Jensen said in a statement.

The mouse models — who were induced with seizures with pentylenetrazol (PTZ) injections and monitored with voltage-sensitive dye (VSD) imaging — were administered AMPA receptor antagonist therapy NBQX. The treatment is an anticonvulsant and antiepileptic that previously showed ability to prevent seizure-induced changes to the neurons of the brain’s hippocampus.

The treatment reduced AMPA receptor enhancement and premature activation of thalamocortical synapses, researchers noted. It also restored synaptic plasticity during the critical period between seizure events and synapses activation, which researchers believe will lead to a better understanding of how early manipulations of silent synapses impact neurological development.

Researchers expressed hope to further pursue understanding of how these associations — and proven measures to prevent them — play into the unknown factors of neurodevelopmental disorder etiology and care.

"This is proof of principle that synaptic plasticity is a dynamic target for the treatment of autism and intellectual disabilities that accompany early-life seizures,” Jensen said. “Further exploration will not only gain more insight into the etiology and treatment of autism, but also other neurodevelopmental disorders.”

The study, "Early Seizures Prematurely Unsilence Auditory Synapses to Disrupt Thalamocortical Critical Period Plasticity," was published online in Cell Reports this week.