The gene PTEN has emerged as one of the most significant autism risk genes. Variations in this gene are found in a significant proportion of people with autism who also exhibit brain overgrowth. Researchers at the Max Planck Florida Institute for Neuroscience have discovered how loss of this gene rewires circuits and alters behavior, leading to increased fear learning and anxiety in mice – core traits seen in ASD.

PTEN has been linked to alterations in the function of inhibitory neurons in the development of ASD. The researchers focused on the changes in the central lateral amygdala driven by loss of PTEN in a critical neuronal population – somatostatin-expressing inhibitory neurons. They found that deleting PTEN specifically in these interneurons disrupted local inhibitory connectivity in the amygdala by roughly 50% and reduced the strength of the remaining inhibitory connections.

This diminished connectivity between inhibitory connections within the amygdala was contrasted by an increase in the strength of excitatory inputs received from the basolateral amygdala, a nearby brain region that relays emotionally-relevant sensory information to the amygdala. Behavioral analysis demonstrated that this imbalance in neural signaling was linked to heightened anxiety and increased fear learning, but not alterations in social behavior or repetitive behavior traits commonly observed in ASD.

The results confirm that PTEN loss in this specific cell type is sufficient to induce specific ASD-like behaviors and provide one of the most detailed maps to date of how local inhibitory networks in the amygdala are affected by genetic variations associated with neurological disorders. Importantly, the altered circuitry did not affect all ASD-relevant behaviors – social interactions remained largely intact – suggesting that PTEN-related anxiety and fear behaviors may stem from specific microcircuit changes.

By teasing out the local circuitry underlying specific traits, researchers hope to differentiate the roles of specific microcircuits within the umbrella of neurological disorders, which may one day help in developing targeted therapeutics for specific cognitive and behavioral characteristics. In future studies, they plan to evaluate these circuits in different genetic models to determine if these microcircuit alterations are convergent changes that underlie heightened fear and anxiety expression across diverse genetic profiles.

CRISPR technology has revolutionized genetics research, enabling scientists to edit genes with unprecedented precision. Recently, researchers at Kobe University developed a new method for modifying embryonic stem cells using CRISPR, creating a bank of 63 mouse embryonic stem cell lines containing the mutations most strongly associated with autism spectrum disorder (ASD). This breakthrough achievement has shed light on the hidden causes of ASD.

For decades, scientists have known that genetics play a significant role in the development of ASD. However, pinpointing the precise cause and mechanism remained elusive due to the lack of a standardized biological model for studying the effects of different mutations associated with the disorder. To address this challenge, Takumi Toru and his team at Kobe University embarked on a journey to create a reliable model by combining conventional manipulation techniques for mouse embryonic stem cells with CRISPR gene editing.

The new method proved highly efficient in making genetic variants of these cells, allowing the researchers to produce 63 mouse embryonic stem cell lines containing the mutations most strongly associated with ASD. These cell lines were further developed into various cell types and tissues, even generating adult mice with their genetic variations. The analysis of these cell lines revealed that autism-causing mutations often result in neurons being unable to eliminate misshapen proteins.

This finding is particularly interesting since the local production of proteins is a unique feature in neurons, and a lack of quality control of these proteins may be a causal factor of neuronal defects in ASD. Takumi expects that this achievement will be an invaluable resource for researchers studying autism and searching for drug targets. Moreover, the genetic variants studied are also implicated in other neuropsychiatric disorders such as schizophrenia and bipolar disorder, making this library potentially useful for studying these conditions as well.

This research was funded by various organizations, including the Japan Society for the Promotion of Science and the National Center of Neurology and Psychiatry. The study demonstrates the potential of CRISPR technology to reveal the hidden causes of complex diseases like ASD, paving the way for future discoveries and treatments.

The Brain’s Hidden Patterns: Uncovering the Secret to Flexibility and Stability

For decades, scientists believed that the brain used a single, shared transmission site for all types of plasticity. However, a groundbreaking study from researchers at the University of Pittsburgh has challenged this assumption, revealing that the brain employs distinct transmission sites to achieve different types of plasticity.

The study, published in Science Advances, offers a deeper understanding of how the brain balances stability with flexibility – a process essential for learning, memory, and mental health. By uncovering the hidden patterns of the brain’s transmission sites, researchers hope to shed light on the underlying mechanisms that govern our thoughts, emotions, and behaviors.

Neurons communicate through synaptic transmission, where one neuron releases chemical messengers called neurotransmitters from a presynaptic terminal. These molecules travel across a microscopic gap called a synaptic cleft and bind to receptors on a neighboring postsynaptic neuron, triggering a response.

Traditionally, scientists believed that spontaneous transmissions (signals that occur randomly) and evoked transmissions (signals triggered by sensory input or experience) originated from one type of canonical synaptic site and relied on shared molecular machinery. However, the research team led by Oliver Schlüter discovered that the brain instead uses separate synaptic transmission sites to carry out regulation of these two types of activity.

The study focused on the primary visual cortex, where cortical visual processing begins. The researchers expected spontaneous and evoked transmissions to follow a similar developmental trajectory, but instead found that they diverged after eye opening.

As the brain began receiving visual input, evoked transmissions continued to strengthen. In contrast, spontaneous transmissions plateaued, suggesting that the brain applies different forms of control to the two signaling modes. To understand why, the researchers applied a chemical that activates otherwise silent receptors on the postsynaptic side, causing spontaneous activity to increase while evoked signals remained unchanged.

This division likely enables the brain to maintain consistent background activity through spontaneous signaling while refining behaviorally relevant pathways through evoked activity. This dual system supports both homeostasis and Hebbian plasticity – the experience-dependent process that strengthens neural connections during learning.

“Our findings reveal a key organizational strategy in the brain,” said Yue Yang, a research associate in the Department of Neuroscience and first author of the study. “By separating these two signaling modes, the brain can remain stable while still being flexible enough to adapt and learn.”

The implications could be broad. Abnormalities in synaptic signaling have been linked to conditions like autism, Alzheimer’s disease, and substance use disorders. A better understanding of how these systems operate in the healthy brain may help researchers identify how they become disrupted in disease.

“Learning how the brain normally separates and regulates different types of signals brings us closer to understanding what might be going wrong in neurological and psychiatric conditions,” said Yang.