Summary: Researchers have discovered how to lose the gene linked to autism in a specific set of inhibitory neurons restructure brain circuits linked to fear and anxiety. Using advanced circuit mapping techniques, they discovered that eliminating the PTEN in neurons that express somatostatin of the local inhibition of the tonsil interrupted in 50% while strengthening the excitatory entry of the nearby brain regions.
This imbalance led to greater anxiety and fear of learning in animal models, without affecting social or repetitive behaviors often seen in autism. The study offers one of the most precise maps of how changes in microcircuit can be the basis of different traits related to ASD, opening new doors for specific treatments.
Key facts:
Specific circuit change: the loss of PTEN in somatostatin neurons weakens the local inhibition and amplifies the exciting signals in the central tonsil. Behavior result: altered circuits were linked to the increase in fear and anxiety, but not to changes in social or repetitive behavior.
Source: Max Planck Florida
Researchers from the Max Planck Florida Neuroscience Institute have discovered how the loss of a gene strongly associated with autism and macrocephaly (large head size) wiring and alters the behavior again.
Its findings, published on borders in cell neuroscience, reveal specific circuit changes in the amygdala resulting from the loss of PTEN in inhibitory neurons, providing new ideas about the alterations of the underlying circuit that contribute to greater fear and anxiety.
Pten has become one of the most significant autism risk genes. The variations in this gene are found in a significant proportion of people with autism that also exhibit brain overgrowth, which makes it a key player to understand the differences in brain function.
To investigate the impact of the erroneous regulation of PTEN, researchers have resorted to animal models, where the overall reduction of PTEN results in an altered sociability, repetitive behaviors and greater anxiety that is often associated with ASD in humans.
But understanding how Pten dysfunction results in a specific circuit and behavioral changes has been difficult in animal models that interrupt PTEN throughout the nervous system.
Therefore, the leader of the MPFI Research Group, Dr. McLean Bolton, and her team have focused on changes in the central lateral tonsil driven by the loss of PTEN in a critical neuronal population: inhibitory neurons that express somatostatin.
Alterations in the function of inhibitory neurons have been observed in the development of ASD through human tissue studies such as genetic mice models. In addition, it is known that the PTEN gene regulates the development of inhibitory neurons.
Therefore, a specific cell type interruption in inhibitory neurons was a valuable objective to understand the specific changes of the circuit associated with the TEA.
“Although a specific cell type interruption does not replicate the changes of the entire genome observed in humans, it is essential to examine how genetic risk factors work within different neural circuits,” said Dr. Bolton.
“Understanding these mechanisms is a crucial step towards specific interventions for specific features such as severe anxiety.”
The team, led by Dr. Tim Holford, combined a genetic model that interrupted Pten only in inhibitory neurons containing somatostatin with a single circuit mapping approach previously developed in the laboratory.
This approach measured the electrical responses of individual neurons to the sequential optogenetic activation of hundreds of nearby neurons, allowing a rapid mape of connectivity and resistance with the accuracy of electrical records and the scale of image approaches.
“This is a powerful method that we can use to determine the changes in the connectivity and resistance of local neurons resulting from genetic variations.
“We were interested in discovering how the interruption of Pten signaling in a single cell type would change the way the brain processes information and contributes to the wide ASD phenotype,” Dr. Holford described.
The scientists focused on the circuits in the central tonsil (Cel), a brain region that is known to serve as an inhibitory door in the expression downstream of fear responses, and found surprising results.
The elimination of PTEN specifically in interneurons containing somatostatin interrupted local inhibitory connectivity in CEL in approximately 50% and reduced the resistance of the inhibitory connections that remained.
This decreased connectivity between the inhibitory connections within the CEL was contrasted by an increase in the force of the excitatory inputs received from the basolateral tonsil (Bla), a nearby brain region that transmits emotionally relevant sensory information to the CEL.
The behavioral analysis of the genetic model showed that this imbalance in neuronal signage was related to the greatest anxiety and an increase in learning of fear, but not alterations in social behavior or repetitive behavior features commonly observed in ASD.
The results not only confirm that the loss of PTEN in this type of specific cell is sufficient to induce specific behaviors similar to ASD, but also provides one of the most detailed maps until the date of how local inhibitory networks in the tonsil are affected by the genetic variations associated with neurological disorders.
It is important to note that the altered circuits did not affect all the relevant behaviors for ASD: social interactions remained largely intact, suggesting that anxiety and fear behaviors related to PTEN can come from specific changes in microcircuitors.
As Dr. Holford explains, “when discovering local circuits that underlie specific features, we hope to differentiate the roles of specific microcircuits within the umbrella of neurological disorders, which one day can help develop specific therapy for specific cognitive and behavioral characteristics.
“In future studies, we hope to evaluate these circuits in different genetic models to determine if these microcircuit alterations are convergent changes that underlie the greatest expression of fear and anxiety in various genetic profiles.”
About this news of genetic research, autism and anxiety
Author: Lesley hang
Source: Max Planck Florida
Contact: Lesley hangs – Max Planck Florida
Image: The image is accredited to Neuroscience News
Original research: open access.
“The Pten in Somatostatina neurons regulates fear and anxiety and is necessary for inhibitory synaptic connectivity within the central tonsil” by McLean Bolton et al. Borders in cell neuroscience
Abstract
Pten in Somatostatina neurons regulates fear and anxiety and is required for inhibitory synaptic connectivity within the central tonsil
INTRODUCTION: The phosphatase and tensin counterpart eliminated on chromosome 10 (PTEN) is a negative regulator of the MTOR route and is strongly associated with the Autistic Spectrum Disorder (ASD), with up to 25% of patients with ASD with macrocephaly ASD that house PTEN mutations.
The mice with haploins supply of the germline show behavioral characteristics that resemble ASD, like several models of mice with conditional Knockouts of Pten. Human tissue studies and multiple genetic mice models suggest that the dysfunction of Gabaergic interneurons can play a role in the development of ASD, but precise mechanisms are still difficult to achieve.
PTEN provides an objective for research because it regulates the development of inhibitory neurons that arise from medial node eminence, promoting survival and maturation of Parvalbumin neurons (PV+) at the expense of somatostatine neurons (Som+).
Methods: Here, we investigate how Pten regulates Som+ neurons at the cellular and circuit level in the central side tonsil (CEL), an area that governs the key behavioral symptoms of social anxiety and emotional motivation altered for social commitment through behavioral analysis, electrophysiology and mapping of local circuits of two photons.
Results: We find that eliminating Pten in the Som+ neurons results in high levels of fear and anxiety and decreases the connectivity of the local circuit Cel. Specifically, this manipulation decreased the resistance of connections between individual neurons and altered the distribution of local connections specifically cell type. Unlike the deficit in local inhibitory connections within CEL, the excitatory disc of the main input of CEL, the basolateral tonsil (BL) improved.
DISCUSSION: This combined imbalance of improved excitement and a decrease in local inhibition probably underlies the greatest learning and anxiety of fear we observe in the PTEN-SOM-KO mice.
