August 18, 2021


by: admin


Tags: Autism, brains, Disruptions, Spectrum, thermostat, traits, underpin


Categories: autism

Disruptions to mind’s ‘thermostat’ might underpin autism traits | Spectrum

Neurons are forever trapped in a dance, adjusting their signals to keep up with new information. When the cells change their speed, they have to maintain a delicate balance: if they increase the excitatory signals too much, it can lead to seizures; too much inhibition can lead to depressive or catatonic states.

Neurons achieve this balance through processes collectively known as homeostatic plasticity. Like a thermostat, this set of controls continuously selects excitatory and inhibitory signals as needed via our neural circuits up or down. Homeostatic plasticity explains how our brain remains plastic and still retains its basic functions over time. It could also modulate autism traits, some experts say.

Over the past decade, research has shown that turning off different genes associated with autism in different brain regions and cell types can disrupt homeostatic plasticity – results suggesting that it is a point of convergence for multiple forms of the disease. This work has also shown how homeostatic disorder leads to signal disturbance, which, according to a popular theory, causes some of the characteristic features of autism, including sensory hypersensitivity and motor difficulties.

Individual differences in homeostatic plasticity could even explain why autism traits vary so widely in people with the same genetic mutation, some scientists speculate.

“I don’t think there is any direct data on this, but it would certainly be a very good hypothesis,” says Peter Kind, Professor of Developmental Neuroscience at the University of Edinburgh. The factors that cause variability in autism – including a person’s environment and genetic background – can also affect the regulation of brain circuitry, Kind says. “Different mechanisms of homeostasis in different people could explain some of the differences in variability and resistance in the expression of a particular genetic mutation that causes autism.”

So tempting, the connection between homeostatic plasticity and autism is far from certain. Researchers deal with scientific and methodological questions. And, with the exception of a few in vitro studies with human stem cells, much of the evidence comes from working on animal models, says Laura Andreae, a lecturer in brain development and autism at King’s College London. How this will affect people remains to be seen.

“It’s a great time to be working on it,” says Andreae. “It’s a very emerging field.”

Stable dynamics:

Neurons reset the brain’s thermostat in a number of ways – and studies suggest that some of these mechanisms stagnate in mouse models of autism and related diseases like Fragile X, Rett, and Angelman Syndrome.

For example, when an eye patch removes input from a control mouse’s visual cortex, neurons encoding information from the uncovered eye typically increase their activity and their likelihood of firing to make up for the loss on the other side.

However, no adaptation occurs in mice lacking the autism-related SHANK3 gene, according to a 2020 study led by Gina Turrigiano, professor of vision at Brandeis University in Waltham, Massachusetts. Treating mice with the mood-stabilizing drug lithium restored both homeostatic processes in the mice, Turrigiano and her colleagues found. It also makes repetitive animal behavior easier.

But since SHANK3 has been linked to other neurological and psychiatric disorders, it’s impossible to tell from the results of the study whether these homeostatic changes are specific to autism, she says. “My view is actually [that] SHANK3 is only an essential part of the synaptic machinery. “

Mutations in another autism-linked gene, CHD8, also appear to disrupt homeostatic plasticity in mice, according to a study conducted by Andreae in April. Eliminating a copy of the gene in the animals’ prefrontal cortex – a region of the brain involved in some cognitive features of autism – resulted in a net increase in inhibition, the team found. The effect appeared to result from subdued and less frequent firing of excitatory cells and was most pronounced around 20 days after birth.

“There is increasing evidence that these types of critical windows, when things change, have an impact on subsequent behavior,” says Andreae.

Unexplained homeostatic processes can also cause Rett syndrome, as other works show. The condition, characterized by repetitive behaviors and speech delay, is almost always caused by mutations in MeCP2, which is involved in a homeostatic process called synaptic scaling: blocking the MeCP2 protein in mice prevents their synapses from adapting to signal changes.

Brain sections from mice modeling Angelman syndrome show signs of impaired synaptic plasticity. And in mouse models of Fragile X syndrome, the animals’ neurons become overly excitable, a sign of imbalanced homeostatic processes.

“The immediate assumption is that [these homeostatic changes] which were always thought to be causally connected downstream with the genetic mutation you are investigating, ”says Kind about his own work with fragile X-mice. “But when you find a phenotype, you never really know.”

Compensation mechanisms:

The broader question – whether mutations associated with autism directly disrupt homeostatic plasticity, or whether these changes provide compensation – could be the biggest challenge for the field, says Kind.

Differentiating between the two will be key to developing therapeutics for people with autism, says Kind. Drugs designed to alter what appears to be overly active or inactive areas of the brain could backfire if the activity is actually a compensatory mechanism designed to stabilize the brain.

Some compelling evidence suggests the changes are compensatory. For example, according to a 2019 study, four mouse models all show an increase in the ratio of excitation to inhibition in neurons that process the movement of the whiskers. However, the mice do not show abnormally high neuronal firing rates, as one would expect if the signal shift were due to a direct influence on homeostatic plasticity. Instead, the neurons seem to increase overall excitation in ways that dampen their rate of fire and, to some extent, stabilize it.

“We concluded that, yes, that [excitatory-inhibitory] Ratio changed in autism, ”says Dan Feldman, professor of neurobiology at the University of California, Berkeley, who led the work. “But it looks like it’s changing in a way that successfully stabilizes synaptic function and perhaps the rate of fire.”

To cement the link between autism and homeostatic plasticity, scientists need to study how genes affect multiple brain regions at the same time and find out which cell types drive neuronal changes, says Peter Wenner, professor of cell biology at Emory University in Atlanta.

“The focus in homeostatic plasticity was more on the single cell level,” he says. “But the cell alone is not the critical feature. In my eyes it is the network. “

Some of that work has already begun: researchers are using tools that use multiple electrodes to monitor activity in multiple areas of the brain in free-moving animals, Wenner says. In this way, they could collect data in order to weigh up how different cell types, layers and brain regions react to disturbances in homeostatic plasticity.

Advances could also come from comparative studies with multiple mouse models to find common genes that affect homeostatic plasticity, Feldman adds. “Autism is such a diverse condition. You really need multiple models if you want to understand how a mechanism generally contributes to autism. “

Eventually, when researchers learn more about the mechanisms of various mutations, they can break down autism into smaller categories, some of which are more or less related to homeostatic plasticity, Andreae says. But right now, with myriad genes involved and limited tools to uncover how they interact to produce traits, it’s still difficult to get a holistic understanding of how homeostatic plasticity can be compromised in autistic people.

“It’s hard to find consensus,” says Andreae, “because everyone is still trying to figure out what’s going on.”


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