A study from Weill Cornell Medicine shows that astrocyte receptors affect cognitive function differently in men and women, suggesting the need for gender-specific approaches when developing treatments targeting these brain cells.

Scientists at Weill Cornell Medicine have found the first evidence that receptors in astrocytes, the brain cells that support and regulate neurons, may have opposing effects on cognitive functions in male and female preclinical models. This study highlights the role of astrocytes in contributing to sex-specific brain mechanisms.

Although many studies have examined the behavioral effects of astrocytic receptors, none have looked at whether biological sex plays a role, and most have examined only males. This study published on May 24 Cell Reports challenges the long-standing assumption that astrocyte signaling has similar cognitive effects in both sexes.

Dr. Nan and Steven Sweed is an assistant professor in the Frontotemporal Dementia Research Unit and an associate professor of neuroscience in the Feil Family Brain department. “Our study shows that previously reported cognitive effects in men may not be extrapolated to women,” said Anna G. Orr. . The Helen and Robert Appel Institute for Mind Research and the Alzheimer’s Disease Research Institute at Weill Cornell Medicine.

Changes in astrocytic receptors are observed in a variety of neurological conditions with known sex differences, including neurodegenerative disorders, schizophrenia, stroke, and epilepsy. However, the mechanisms contributing to sex differences are not fully understood.

What is the difference between the male brain and the female brain?

First author and former graduate student in Orr’s laboratory, Dr. The study by Samantha M. Meadows focused on mGluR3, the predominant glutamate receptor in astrocytes and a gene that is upregulated in dementia. The team used gene editing and stimulation of engineered receptors in animal models to selectively manipulate astrocytes and examine the effects of mGluR3-related receptors on learning, memory, and other cognitive and behavioral outcomes.

The researchers found that increasing astrocytic mGluR3 levels improved memory in older women, and reducing these levels was sufficient to impair memory in younger women; This suggested that mGluR3 contributes to memory in women. However, in men, reducing mGluR3 improved memory, while increasing the receptor had no effect. Dr. “Interestingly, the cognitive effects of these receptors are not conserved between genders,” Meadows said.

To understand whether these different effects are specific to mGluR3 or reflect a broader feature of astrocytic receptor signaling, Dr. Meadows is an associate professor of neuroscience at the Brain and Mind Institute and the Appel Alzheimer Research Institute. He studied with Adam L. Orr. to selectively stimulate different receptors on astrocytes while mice perform learning and memory-related tasks.

Surprisingly, the team found additional evidence that activation of the receptors causes memory improvement or impairment depending on biological sex. Dr. “A sex-specific balance of astrocytic signaling appears to be required for normal brain function,” said Adam Orr.

This study suggests that further studies may be needed to evaluate the effects of mGluR3 modulators developed to treat disorders such as schizophrenia and anxiety across gender. Dr. “Therapeutic drugs that affect astrocyte receptors may cause gender-related cognitive effects, in part due to the different roles of astrocytes in men and women,” said Anna Orr.

The lab is investigating what might cause the different effects and whether other brain functions also vary by gender.