Neural signaling protein could be therapeutic target for autism-linked gene deletion

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by Liz Ahlberg Touchstone, University of Illinois at Urbana-Champaign

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The increased amount of the signaling protein PSD-95 found in mice with MEF2C haploinsufficiency leads to increased seizure activity and cognitive deficits. Credit: Nien-Pei Tsai

A particular signaling protein in the brain could be a therapeutic target for neurological disorders arising from the deletion of the autism-linked gene MEF2C, University of Illinois Urbana-Champaign researchers found in a new mouse study published in the journal Proceedings of the National Academy of Sciences.

Deletions or mutations to MEF2C are associated with a number of neurological and developmental disorders, from autism to epilepsy to Alzheimer's disease, said study leader Nien-Pei Tsai, an Illinois professor of molecular and integrative physiology.

MEF2C haploinsufficiency is the term for when someone has only one copy of the gene, rather than the typical two. It is a condition characterized by intellectual disability, autism spectrum disorder and seizures.

"Although MEF2C haploinsufficiency is a rare genetic disorder, the MEF2C protein is associated with many other diseases. Its dysregulation has been linked to many different types of autism," Tsai said. "By understanding MEF2C, hopefully we can increase the knowledge of not just haploinsufficiency, but many other neurodevelopmental disorders associated with MEF2C."

Professor Nien-Pei Tsai led a team that found that a deletion of the MEF2C gene, associated with autism, epilepsy and Alzheimer's disease, increases a signaling protein in the brain—but decreasing or inhibiting that protein reverses symptoms in mice. Credit: Fred Zwicky

Tracing the link to PSD-95

Tsai's previous work found a link between MEF2C haploinsufficiency and the neural signaling protein PSD-95, which also is associated with epilepsy, Alzheimer's and other neurological disorders. In the new work, Tsai's group looked more closely at that link to explore whether PSD-95 could be a therapeutic target for MEF2C deletions.

"MEF2C has an indirect link to regulate the stability of this PSD-95 protein," said Tsai, who also is affiliated with the Beckman Institute for Advanced Science and Technology at the U. of I. "We assumed that if a patient has less MEF2C, the level of PSD-95 will go up, because it's not being degraded like it's supposed to be. We wanted to verify that, and to see what the effect would be if we could then decrease the PSD-95."

The researchers bred mice with only one copy of MEF2C. The mice experienced profound seizures and cognitive impairments, as they lost their ability to recognize novel objects and recognize new mice socially. The researchers found that the levels of PSD-95 were indeed elevated in the brains of the affected mice.

Reducing PSD-95 restored recognition and eased seizures

To determine whether targeting PSD-95 could be an effective strategy for treating those with MEF2C haploinsufficiency, the researchers tried two methods for reducing PSD-95. First, they developed a breed of mice that not only had one copy of MEF2C but also only one copy of the gene for PSD-95, called "knocking down" a gene.

Second, they administered a drug that inhibits PSD-95 from interacting with its receptor in neurons to the mice with MEF2C haploinsufficiency but normal PSD-95.

"Surprisingly, the novel object recognition and the social novelty recognition ability were restored by knocking down or inhibiting PSD-95," said graduate student Meijin Pan, the first author of the paper.

"The severe seizures were restored back to the normal range we see in wild-type mice, as well. That suggests to us that inhibiting PSD-95 could be a therapeutic target to reduce seizures and rescue some cognitive ability in those with MEF2C haploinsufficiency, or other conditions that decrease MEF2C."

Following the NMDA receptor pathway

Tsai's group previously found increased levels of PSD-95 were connected to seizure activity in the early stages of a familial form of Alzheimer's disease, suggesting that this protein plays a critical role in neural function and that its levels must be tightly controlled, Tsai said.

Next, the researchers plan to further explore the role of the receptor that PSD-95 interacts with, called the NMDA receptor, which is a major calcium channel and driver of neural signaling, Pan said. The researchers want to study the downstream effects of excess PSD-95 to identify other possible targets.

"We know that the NMDA receptor is probably more active in MEF2C mouse brains, but we have no idea what that might do to the mice. Hopefully down the road we will be able to identify new targets or probably new drugs that can specifically target this pathway," Tsai said.

Publication details

Meijin Pan et al., Hyperfunction of PSD-95 leads to hyperexcitability and cognitive abnormalities in MEF2C haploinsufficiency, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2606341123

Journal information: Proceedings of the National Academy of Sciences

Key medical concepts

MEF2C GeneSeizuresCognitive Dysfunction

Clinical categories

NeurologyPsychiatryPsychology & Mental healthClinical geneticsChildren's health Provided by University of Illinois at Urbana-Champaign Who's behind this story?

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