Autism spectrum disorder (ASD) is widely known for its core features, which include difficulties in social communication and repetitive behaviors. But beyond these, many individuals with ASD also struggle with comorbid conditions, particularly anxiety. Nearly 40 percent of children with ASD experience anxiety disorders and often show unusually heightened fear responses. Studies have even suggested that people with ASD may be more vulnerable to trauma, unable to “erase” fear memories, which resembles symptoms seen in post-traumatic stress disorder (PTSD).

Until now, most evidence for PTSD-like symptoms in ASD has relied on self-reports, leaving the underlying brain mechanisms unclear. In a new study, researchers led by Professor KIM Eunjoon at the Institute for Basic Science (IBS) have uncovered how an ASD-related mutation in the Grin2b gene, which encodes the GluN2B subunit of NMDA receptors, disrupts brain circuits that normally extinguish fear. Their findings, published in Science Advances, provide the first detailed mechanistic explanation for why ASD increases PTSD risk.

The team used mice carrying a human ASD-linked mutation in Grin2b. These mice learned fear memories normally after a traumatic experience, but were unable to extinguish them. As a result, they displayed exaggerated long-term fear responses — closely resembling PTSD.

Brain mapping revealed that the basal amygdala (BA), a key hub for fear-memory extinction, became abnormally silent after trauma in mutant mice.

“These animals could learn fear just fine, but they couldn’t unlearn it,” said Kim. “The amygdala essentially shut down when it was needed most, leaving the traumatic memory locked in place.”

Electrophysiological studies showed that after trauma, BA excitatory neurons in mutant mice exhibited suppressed synaptic activity and reduced excitability. This dysfunction prevented the brain from erasing fear.

To test whether this silencing caused the PTSD-like behavior, the team used chemogenetic tools to artificially reactivate BA neurons during extinction training. Remarkably, this restored excitatory signaling, normalized neuronal activity, and rescued both fear-memory extinction and long-term fear responses.

“These results show that the silenced amygdala after trauma is the root of PTSD-like symptoms in our model,” explained co-first author KANG Muwon. “By reactivating those neurons, we could reverse the behavioral and physiological abnormalities.”

The researchers took care to ensure that viral tools used to manipulate neurons did not themselves interfere with results. They carefully calibrated doses and repeated experiments to confirm reliability. Interdisciplinary collaboration with other groups also helped pinpoint the basal amygdala as the disease-relevant brain region.

This study is the first to establish the molecular and circuit-level mechanisms underlying PTSD-like symptoms in autism. By showing that a mutation in Grin2b silences amygdala neurons after trauma — and that reactivation can reverse this effect — the research provides valuable clues for future therapies.

“This work bridges a crucial gap,” said Kim. “We move from anecdotal reports of trauma vulnerability in autism to a clear mechanistic understanding of why it happens, and even show that it can be reversed in a model system.”

The team plans to extend their work by combining transcriptomic and proteomic analyses to examine gene expression changes in BA excitatory neurons after trauma. They also intend to test receptor-specific agonists and antagonists targeting GluN2B-containing NMDA receptors, which may further illuminate therapeutic pathways.

Figure 1. Fear-memory extinction and remote fear-memory responses are regulated by the activity of basal amygdala excitatory neurons
In normal mice, after a traumatic event, the synaptic network complex and excitability of basal amygdala excitatory neurons increase, which activates the basal amygdala, facilitating the extinction of fear-memory and preventing remote fear-memory responses (left). However, in Grin2b mutant autistic mice, the synaptic network complex and excitability of basal amygdala excitatory neurons do not increase after a traumatic event, suppressing the activation of the basal amygdala, hindering the extinction of fear-memory, and resulting in enhanced remote fear-memory responses (middle). When the basal amygdala is artificially activated during the extinction process of fear-memory, the synaptic network complex and excitability of basal amygdala excitatory neurons increase, resulting in the rescue of fear-memory extinction and alleviating remote fear-memory responses (right).