October 21, 2021

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by: admin

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Tags: Autismlinked, gene, learning, molds, plasticity, Spectrum, synaptic, SYNGAP1

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Categories: autism

Autism-linked gene SYNGAP1 molds synaptic plasticity, studying | Spectrum

Bouton bust: SYNGAP1 helps neurons eliminate old synapses and form new ones after a new experience (left and center left) – a process that is attenuated in mice lacking a copy of the gene (center right and right).

Courtesy Gavin Rumbaugh

In fact, according to a new study in mice, partial loss of the autism-linked SYNGAP1 gene affects the brain’s ability to respond to sensory experiences. The finding could help explain why people with SYNGAP1 mutations tend to have learning difficulties and high pain tolerance.

The protein SYNGAP1 is rich in stimulating synapses, where it shapes plasticity and helps neighboring neurons to strengthen or weaken their connections. So far, however, it has been unclear how SYNGAP1 affects “ensembles”, groups of neurons with coordinated activity that are considered to be the “direct neural correlate of behavior and thinking,” says lead researcher Gavin Rumbaugh, professor of neuroscience at Scripps Research in Jupiter. Florida.

To encode new information about a sensory experience, a neural ensemble must redistribute its activity: some neurons increase their chatter while others switch it down to keep the overall activity of the group the same. “Basically, it’s learning,” says Rumbaugh.

This redistribution is no longer present in mice missing a copy of SYNGAP1, as the new work shows. Only the decrease in activity occurs, which leads to an overall weakened ensemble. However, restoring typical SYNGAP1 expression levels in adult model mice normalizes the distribution of activity, the team found.

“It really shows that SYNGAP1 does play a role in the mature brain,” said Kimberly Huber, a neuroscience professor at Southwestern Medical Center at the University of Texas at Dallas, who was not involved in the work.

New sensations:

Rumbaugh and colleagues used calcium imaging to record the ensembles that activate when mice receive a gentle touch of their whiskers. The team found that the neurons in these ensembles could be divided into three groups: more than half of the cells were weakly active during whisker stimulation, around 30 percent were moderately active, and around 7 percent were highly active. This pattern of activity remained the same in both wild-type and SYNGAP1-deficient mice when the researchers recorded from the same neurons 13 days later.

“That says that if you don’t give the animal a new experience, these ensembles are basically stable,” says Rumbaugh.

The team then cut all but one mustache on each mouse and returned the animals to their cages – a move Rumbaugh compared to numbing three fingers and a thumb on a person’s hand and asking them to identify objects by they rummaged their hand through a pocket: -familiar experiences would suddenly feel new.

As expected, the total activity of the ensembles did not change in the wild-type mice, but the distribution of the ensemble activity did: The weakly active cells increased their fire, the highly active cells suppressed their reactions dramatically and the moderately active cells showed small changes.

Similarly, in the SYNGAP1 mice, the highly active cells grew more quietly and the moderately active cells remained stable. But the weakly active cells did not increase their signaling after the new experience, Rumbaugh and his colleagues found.

“That’s the twist. And it has a complex impact on the circuit, ”says Richard Huganir, director of neuroscience at Johns Hopkins University in Baltimore, Maryland, who was not involved in the study.

Rather than the overall activity of the ensemble remaining stable in response to the new experience, the lack of SYNGAP1 weakens the activity, which could explain why SYNGAP1 mice have poor whisker-dependent learning, as Rumbaugh and colleagues previously reported.

Learning curve:

Wild-type mouse neurons that activate simultaneously strengthen their synapses, as further experiments in pairs of cultured cells showed; Neurons that become slightly asynchronous weaken their connection.

In contrast, neurons from mice lacking a copy of SYNGAP1 weaken their connection with cells that fire out of sync, but do not strengthen their connection with those that activate simultaneously – suggesting that the gene is essential for this mechanism .

Wild-type mice also have additional presynaptic boutons – the nubs on a neuron that synapse with other cells – according to a new sensory experience the team found using two-photon imaging. Instead, SYNGAP1-deficient mice respond with less presynaptic boutons.

“SYNGAP1 has to stimulate a mechanism that increases synaptic input into these networks and creates new synapses,” says Rumbaugh. “We believe that these weakly active neurons therefore cannot increase the whisker experience” in the SYNGAP1-deficient mice.

SYNGAP1 mice, engineered so that the silenced copy of the gene can be restored in adulthood, have ensemble activity similar to that of wild-type mice, the team also found.

That suggests that the potential window for treating people with SYNGAP1 mutations extends beyond early development, says Huganir.

It also indicates the possibility of harnessing SYNGAP1’s ability to strengthen synapses and improve learning in other situations, Rumbaugh says. He and his colleagues are looking for compounds that can increase SYNGAP1 expression.

“We believe they will be cognitive enhancers,” which will make the overall plasticity of the ensemble more efficient overall, he says.

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