Mouse model unveils dynamics through which SYNGAP1 gene supports cognitive function microbiologystudy

The SYNGAP1 gene, which supports the production of a protein called SynGAP (Synaptic Ras GTPase-Activating Protein), is known to play a key role in supporting the development of synapses and neural circuits (i.e., connections between neurons). Mutations in this gene have been linked to various learning disabilities, including intellectual disabilities, speech and language delays, autism spectrum disorder (ASD), and epilepsy.

Researchers at the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology recently carried out a study aimed at better understanding the genetic mechanisms via which the SYNGAP1 gene contributes to healthy cognitive function. Their findings, published in Nature Communications, suggest that the autonomous expression of this gene in the cortical excitatory neurons of mice promotes the animals’ cognitive abilities via the assembly of long-range neural circuits integrating sensory and motor information.

“Our paper builds on our ongoing research into how major risk genes for mental health disorders, including autism, regulate brain organization and function,” Gavin Rumbaugh, senior author of the paper, told Medical Xpress. “The field knows the major risk genes that directly contribute to cognitive and behavioral impairments that lead to diagnosable forms of autism and related neuropsychiatric disorders in humans.

“When these genes are dysfunctional, this process leads to a genetic disorder that results in one of several possible neurological and/or psychiatric diagnoses—epilepsy, intellectual disability, autism, for example.”

Observed mutations in the SYNGAP1 gene are known to inactivate one of the two copies of this gene that are inherited from each parent. This ‘de-activation’ via a ‘de novo’ (i.e., new) mutation results in only half of SYNGAP1 messages ultimately being converted into the production of the SynGAP protein.

As the SynGAP protein supports the development and strengthening of synapses, enabling healthy communication between neurons, the lower production of this protein can adversely impact brain function. Essentially, it was found to disrupt how neurons communicate with each other and, thus, how information travels through the brain.

“The results are the phenotypes described in SYNGAP1 patients,” said Rumbaugh. “What we do not understand, for this or any other genetic neurodevelopmental disorder, is how, when, and where in the brain these genes act to disrupt specific aspects of brain function required to produce ‘thinking’ and resultant ‘behavioral adaptation.”

What type of neurons are sensitive to these genes? What circuits do they form and how do these circuits come together into networks that process information required for thinking and changing our behavior?”

To answer these research questions, neuroscientists need to conduct experiments on animals expressing the same gene variants found in humans exhibiting SYNGAP1 genetic mutations. Subsequently, they should closely assess brain function time-locked to specific behavioral events that reflect adaptation to the environment, such as exploring objects and making decisions based on what was learned through sensory exploration.

“SYNGAP1 patients have very clearly altered sensory processing—they do not react to sensory experience the same way as a typically developing individual,” explained Rumbaugh.

“Their brains do not produce effective defensive behaviors to painful stimuli. Their brains do not adequately process risk within the environment. This results in them carrying out behaviors that jeopardize their health and safety. They also do not form effective language.”

These three deficits (i.e., a lack of defensive behaviors in response to painful stimuli, the impaired assessment of risk and the inability to form language) are thought to be related to the processing of sensory information to create a “plan,” which the brain then converts into a motor response. This is essentially a planned “program” for how an animal’s body will move based on available sensory information, allowing it to continuously adapt to a rapidly changing and unpredictable environment.

As part of their study, Rumbaugh and his colleagues conducted experiments on a mouse model of the SYNGAP1 genetic disorder observed in humans. These experiments were designed to closely examine the circuit mechanisms that link the expression of the SYNGAP1 gene to abnormal sensory processing and how this degrades cognitive performance and adaptative behavior.

“This paper is a significant advance in that it provides insight at the circuit and network levels with respect to how genes like Syngap1 promote wiring brains to enable higher cognitive functions, such as sensory perception,” said Rumbaugh.

“Perception is an emergent neurocognitive process within neural networks where sensory information obtained from an experience is assigned meaning so that a behavioral response can be formulated. This is an essential process that enables animals, including humans, to adapt to the environment; a process that is disrupted in developmental disorders like autism and intellectual disability.”

Overall, the findings gathered by this team of researchers suggest that the autonomous expression of Syngap1 in mouse cortical excitatory neurons supports attention-based tactile object exploration and tactile learning. Using advanced behavioral tasks, Rumbaugh and his colleagues were able to directly connect altered perceptual behaviors in mice to changes in how tactile information was coded in the cerebral cortex.

“We performed in vivo physiology in the somatomotor cortical-thalamic network in this model as animals explored objects during active touch,” said Rumbaugh. “We found that Syngap1 expression in the cortex regulates neural dynamics within this system. This told us that sensory processing in the cortex was disrupted, not sensory coding, which happens in the body. Of note, we found that touch encoding was upside down in Syngap1 models.

“In mice, monkeys, and humans, weak exploratory touches induce low spike rates in cortical ‘touch’ neurons, while strong touches drive high spike rates in these same neurons (and this is what we found in WT mice). This is how the cortex assigns meaning to mechanical touches, such as texture, position, or shape. In Syngap1 model mice, this process was inverted—weak touches drove high spike rates, while strong touches drove low spike rates.”

The researchers are still unsure about how the processes they observed in mice take place at a neural circuit level, and they plan to explore this further in future papers. However, they were able to identify circuit-specific defects in the Syngap1 mouse model they used, which were specific to the cortical thalamic touch network.

“We found that there was pervasive cortical hyperconnectivity from motor cortex connections back to somatosensory cortex,” said Rumbaugh. “However, there was hypoconnectivity from sensory thalamus connections into somatosensory cortex. Thus, Syngap1 mutations linked to the human disorder accentuate motor feedback into a sensory cortex that improperly codes for touch experiences.”

In the mouse model examined by Rumbaugh and his colleagues, the animal’s sense of touch appears to no longer provide the information necessary to support effective decision-making. As a result, motor signals linked to tactile information are “dialed up,” which translates into an impaired ability to form plans and execute adaptive behavior plans.

“This disrupted sensory experience might be akin to wearing a glove while trying to differentiate between two similar objects using only your sense of touch,” explained Rumbaugh. “It would be hard to figure out what is different between the objects, but because the Syngap1 mouse brain also has a problem with impulsive responding, the animal makes a series of incorrect choices.

“One would expect this to be very frustrating at an emotional level because the animals are thirsty (to provide motivation), yet the only way to get a drink is to give the correct answer. This puts into perspective how one may experience life if they have a genetic variant that leads to autism with intellectual disability.”

The recent paper by this team of researchers contributes to understanding processes via which genes, particularly the SYNGAP1 gene, regulate sensory processing, which can affect goal-directed behavioral responses. In the future, it could serve to inspire additional research focusing on the reported cortical sensorimotor dynamics, which could enrich the present understanding of human SYNGAP1 disorders or other genetic disorders that lead to intellectual disability with autism.

“With a few exceptions, studies before ours mainly looked at sensory processing in the absence of goal-directed behaviors. They assessed how motor control issues lead to erroneous responses, or how sensory processing impacts reflexive behaviors (unconscious movements in response to unexpected sensory signals),” added Rumbaugh.

“In our next studies, we plan to expand this work to other genetic models. We also plan to perform dense electrophysiological recordings across the entire brain of Syngap1 mice as a tool to screen for dysfunctional circuits that underlie aspects of brain function that are linked to autistic traits and cognitive impairment.”

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