The Social Fear Gene: How One Mutation Can Rewire The Brain And Increase Anxiety

Scientists have discovered that a mutation in the PTEN gene, linked to autism, can cause imbalances in neurons that control emotions, particularly in the amygdala, a brain region linked to fear and anxiety. In tests on mice, the lack of this gene in certain neurons increased levels of anxiety and fear, helping to better understand how brain changes can influence autism symptoms.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects approximately 1 in 36 children in the United States. It primarily manifests as difficulties with social interaction and communication, repetitive behaviors, or very restricted interests.

However, many individuals with autism spectrum disorder also experience other associated symptoms, such as seizures, anxiety, cognitive difficulties, sensitivity to sensory stimuli, and abnormal brain growth (macrocephaly).

Science has already identified more than 100 genes linked to the risk of developing autism spectrum disorder, and one of the most studied is the PTEN gene, which regulates cell growth and acts directly on a cellular pathway called mTOR. Mutations in this gene are present in up to 25% of people with autism spectrum disorder who also have macrocephaly.

Animal research has shown that when there are alterations in the PTEN gene in mice, they develop behaviors similar to those seen in people with autism spectrum disorder, such as anxiety, social difficulties, and repetitive movements.

These animals also exhibit physical changes in the brain, such as increased neuron size, a greater number of synaptic connections, and altered brain activity. Depending on which type of neuron has the PTEN gene deactivated (known as a "knockout"), different behavioral and brain effects are observed.

A major focus of recent research is inhibitory neurons, cells that help "slow down" brain activity, which utilize a substance called GABA. These neurons play an essential role in balancing brain activity and controlling anxiety, attention, and emotional response. Among them, two types have gained attention: those that produce parvalbumin (PV+) and those that produce somatostatin (SOM+).

While the PTEN gene appears to favor the development of PV+ neurons, it can inhibit the growth or function of SOM+ neurons. When this balance between the two types of neurons is altered, the brain can become dysregulated, which may contribute to the symptoms of autism spectrum disorder.

In the study described, scientists investigated exactly what happens when the PTEN gene is removed only from SOM+ neurons in a brain region called the central lateral amygdala (CeL). This area is responsible for regulating emotional responses, such as fear and anxiety, which are often altered in people with autism spectrum disorder.

They used genetically modified mice and observed their behavior, measured neuron activity, and mapped the connections between them using a sophisticated technique called two-photon circuit mapping.

The results showed that the lack of the PTEN gene in SOM+ neurons led to increased anxiety and fear in the mice. Furthermore, local connections between neurons in the CeL became weaker and less organized.

Interestingly, while this part of the brain lost strength in its braking (inhibition) network, input from another region, the basolateral amygdala (BLA), which sends excitation signals, became stronger. This imbalance between excitation and inhibition appears to be one of the factors explaining the more anxious and reactive behavior of these mice.

This figure shows how removing the PTEN gene from certain neurons called SOM+ affects communication between two brain regions involved in fear and anxiety: the basolateral amygdala (BLA) and the central lateral amygdala (CeL). In image (a), we see a schematic of the experiment, where scientists used a technique called optogenetics (activating neurons with light) to stimulate connections from the basolateral amygdala to SOM+ neurons in the central lateral amygdala. In graph (b), the researchers measured the electrical signals generated by this stimulation and found that, in mice without the PTEN gene (KO), SOM+ neurons received slightly stronger signals than normal (WT) mice, but this difference was not statistically significant. In graph (c), they assessed the type of excitatory signal and found that the KO mice had a much higher ratio of AMPA/NMDA receptors, indicating a change in how these neurons process stimuli, suggesting greater excitatory activation. Finally, in graph (d), they tested whether the likelihood of releasing neurotransmitters changed, and found no difference between the groups.

In summary, this study shows that specific alterations in the functioning of a type of inhibitory neuron, due to the absence of the PTEN gene, can lead to profound changes in the organization of brain circuits related to emotion and social behavior.

This helps to better understand the biological mechanisms that may underlie autism symptoms and points to new avenues for research and treatment.

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PTEN in somatostatin neurons regulates fear and anxiety and is required for inhibitory synaptic connectivity within central amygdala

Timothy W. Holford, Kaitlyn N. Letourneau, Carolyn Von-Walter, Daniela Moncaleano, Cody L. Loomis, and M. McLean Bolton

Front. Cell. Neurosci., 26 June 2025, Volume 19 - 2025

https://doi.org/10.3389/fncel.2025.1597131

Abstract: 

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of the mTOR pathway and is strongly associated with autism spectrum disorder (ASD), with up to 25% of ASD patients with macrocephaly harboring PTEN mutations. Mice with germline PTEN haploinsufficiency show behavioral characteristics resembling ASD, as do various mouse models with conditional knockouts of PTEN. Human tissue studies and those from multiple genetic mouse models suggest that dysfunction of GABAergic interneurons may play a role in the development of ASD, but the precise mechanisms remain elusive. PTEN provides a target for investigation because it regulates the development of inhibitory neurons arising from the medial ganglionic eminence, promoting the survival and maturation of parvalbumin (PV+) neurons at the expense of somatostatin (SOM+) neurons. Here, we investigate how PTEN regulates SOM+ neurons at the cellular and circuit level in the central lateral amygdala (CeL), an area that governs the key ASD behavioral symptoms of social anxiety and altered emotional motivation for social engagement using behavioral analysis, electrophysiology, and two-photon local circuit mapping. We found that knocking out PTEN in SOM+ neurons results in elevated levels of fear and anxiety and decreases CeL local circuit connectivity. Specifically, this manipulation decreased the strength of connections between individual neurons and altered the distribution of local connections in a cell-type specific manner. In contrast to the deficit in local inhibitory connections within CeL, the excitatory drive from the major CeL input, the basolateral amygdala (BLA) was enhanced. This combined imbalance of enhanced excitation and diminished local inhibition likely underlies the heightened fear learning and anxiety we observed in the PTEN-SOM-KO mice.