Autism spectrum disorder (ASD), a neurodevelopmental condition predominantly characterized by challenges in social communication and repetitive behaviors, has long been associated with heightened sensitivity to anxiety and fear-related disorders. Emerging research now highlights an intricate intersection between ASD and post-traumatic stress disorder (PTSD), two conditions previously studied largely in isolation. In a groundbreaking study led by Professor Eunjoon Kim of the Institute for Basic Science (IBS), scientists have unveiled the neural underpinnings that may explain why individuals with ASD experience amplified susceptibility to PTSD-like symptoms. Their findings elucidate how mutations in the Grin2b gene disrupt normal neural circuits responsible for extinguishing fear, revealing critical insights into anxiety comorbidities in autism.
The core of this discovery lies in the role of the basal amygdala (BA), a central hub in the brain implicated in processing and regulating fear memories. In typical brains, exposure to traumatic events prompts increased synaptic complexity and heightened excitability of excitatory neurons within the BA. This chain of neural activity facilitates the extinction of fear memories, effectively “erasing” maladaptive responses over time. However, in mice harboring a human ASD-associated mutation in Grin2b—a gene encoding the GluN2B subunit of NMDA receptors—this adaptive mechanism is profoundly altered. Despite forming fear memories normally, these mutant animals fail to extinguish them, resulting in persistent and enhanced long-term fear reminiscent of PTSD pathology.
Electrophysiological analyses provided a window into the cellular deficits underpinning this phenomenon. Following traumatic stimuli, BA excitatory neurons in Grin2b-mutant mice displayed suppressed synaptic transmission and a marked reduction in neuronal excitability. These changes indicate a silencing of the amygdalar network precisely when heightened activity would be necessary to overwrite fear memories. The failure to activate these circuits effectively “locks in” the traumatic experience, preventing the natural attenuation of fear responses and perpetuating chronic anxiety.
Importantly, the study employed chemogenetics—a cutting-edge technique that allows selective modulation of neuronal activity via engineered receptors responsive to designer drugs—to assess causality in this process. By artificially stimulating the BA excitatory neurons during extinction learning, researchers successfully restored synaptic activity and neuron excitability. This targeted reactivation not only normalized neural signaling but also rescued behavioral deficits, enabling mice to extinguish fear memories and diminish pathological fear responses. Such evidence underscores the centrality of amygdalar dysfunction in ASD-related PTSD vulnerability and opens avenues for therapeutic intervention.
These results offer a mechanistic explanation for clinical observations where individuals with autism report exaggerated and enduring fear or anxiety, often mirroring PTSD symptomatology. Until now, the convergence of ASD and trauma-related disorders has been poorly understood at the circuit and molecular levels, with much reliance on patient self-reports and epidemiological associations. The IBS team’s approach reveals a direct link between Grin2b mutation-induced receptor dysfunction, altered synaptic physiology in the amygdala, and disrupted fear-memory processing, bridging a critical knowledge gap.
Professor Kim elaborates that these findings illuminate why amygdalar hypoactivity, rather than hyperactivity, can underlie PTSD-like phenotypes in this autism model. While excessive amygdala activation has traditionally been associated with anxiety disorders, here the silencing of key excitatory neurons presents an alternative pathophysiological mechanism. This insight challenges previous models and suggests that effective treatments might need to strategically enhance amygdalar excitability rather than suppress it.
To ensure robustness, the research team meticulously controlled for potential confounds, verifying that viral vectors used for chemogenetic manipulation did not introduce artifacts affecting neuronal function. Cross-disciplinary collaboration aided in precisely identifying the BA as the pivotal brain region implicated. This comprehensive approach strengthens the validity of the conclusions and provides a solid foundation for translational applications.
Looking ahead, the researchers plan to integrate transcriptomic and proteomic analyses to map molecular changes within BA excitatory neurons after trauma exposure. Such investigations will help identify specific gene expression profiles and signaling pathways influenced by Grin2b mutations, offering further insight into the molecular cascade driving synaptic and functional alterations. Additionally, pharmacological studies targeting GluN2B-containing NMDA receptors with selective agonists or antagonists aim to delineate receptor-specific roles in fear memory regulation.
This pioneering work not only deepens our understanding of fear-memory extinction mechanisms in the context of autism but also highlights potential therapeutic targets. Reactivating silenced amygdala circuits may prove a viable strategy to mitigate PTSD-like symptoms in individuals with ASD, addressing a critical unmet need in clinical management. The ability to reverse behavioral and physiological deficits in a mouse model through targeted neuronal stimulation carries profound implications for future clinical therapies.
In sum, the study represents a major advance in neuroscience, synthesizing molecular genetics, electrophysiology, and chemogenetics to unravel a complex neuropsychiatric phenomenon. By detailing how a single gene mutation disrupts neuronal networks responsible for fear extinction, it sets the stage for novel approaches to treat anxiety and trauma-related disorders in autism. This work not only bridges gaps in fundamental science but also offers hope for interventions improving quality of life for millions affected by these intertwined conditions.
As Professor Kim reflects, this research underscores the transformative potential of mechanistic investigation in mental health. “By moving beyond descriptive symptoms to causative pathways, we can forge new therapeutic avenues where none existed before.” The confluence of genetics, circuit biology, and behavioral neuroscience promises to redefine our understanding of fear, memory, and resilience in autism spectrum disorder.
Subject of Research: Neural mechanisms underlying PTSD-like symptoms in autism spectrum disorder caused by Grin2b mutations affecting basal amygdala neuronal function.
Article Title: Grin2b-mutant mice exhibit heightened remote fear via suppressed extinction and chronic amygdalar synaptic and neuronal dysfunction
News Publication Date: 17-Sep-2025
Web References:
http://dx.doi.org/10.1126/sciadv.adr7691
Image Credits: Institute for Basic Science
Keywords: Autism, Developmental disabilities, Post traumatic stress disorder, Amygdala, Fear, Excitatory synapses, Neuronal synapses, Neurons, Brain structure, Psychiatric disorders, Clinical psychology, Central nervous system
