Scientists at Weill Cornell Medicine have discovered groundbreaking evidence that astrocyte receptors can have opposite effects on cognitive function in male and female preclinical models. This finding highlights the significant role of astrocytes—brain cells that support and regulate neurons—in sex-specific brain mechanisms.
Traditionally, studies have focused on the behavioral effects of astrocytic receptors, predominantly in males, without considering the influence of biological sex. However, this new study, published on May 24 in Cell Reports, challenges the longstanding assumption that astrocytic signaling has uniform cognitive effects across sexes.
“Our study reveals that previously reported cognitive effects in males can't be extrapolated to females,” said Dr. Anna G. Orr, the Nan and Stephen Swid Assistant Professor of Frontotemporal Dementia Research, and an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute and the Helen and Robert Appel Alzheimer's Research Institute at Weill Cornell Medicine.
Astrocytic receptor changes are observed in various neurological conditions that exhibit sex differences, including neurodegenerative disorders, schizophrenia, stroke, and epilepsy. Despite these observations, the mechanisms driving sex differences remain poorly understood.
Investigating sex differences in brain function
Dr. Samantha M. Meadows, the study's first author and a former graduate student in Dr. Orr's lab, centered her research on mGluR3, a predominant glutamate receptor in astrocytes and a top altered gene in dementia. Using gene editing and stimulation of engineered receptors in animal models, the team selectively manipulated astrocytes to investigate the effects of mGluR3 and related receptors on learning, memory, and other cognitive and behavioral outcomes.
The study revealed that increasing astrocytic mGluR3 levels improved memory in older female models, while reducing these levels impaired memory in young females, indicating that mGluR3 promotes memory recall in females. Conversely, in male models, reducing mGluR3 enhanced memory, whereas increasing the receptor had no effect.
“Interestingly, the cognitive impact of these receptors is not conserved among sexes,” Dr. Meadows noted.
To determine if these divergent effects were unique to mGluR3 or indicative of a broader characteristic of astrocytic receptor signaling, Dr. Meadows collaborated with Dr. Adam L. Orr, an assistant professor of research in neuroscience. Together, they selectively stimulated different astrocytic receptors while mice performed tasks involving learning and memory.
Surprisingly, the team found further evidence that receptor activation caused either memory enhancement or impairment depending on biological sex. “Normal brain function seems to require a sex-specific balance in astrocytic signaling,” said Dr. Adam Orr.
Implications for therapeutic development
These findings suggest that mGluR3 modulators currently being developed for treating disorders such as schizophrenia and anxiety may need additional study to assess their sex-specific impacts. “Therapeutics influencing astrocytic receptors may cause sex-specific cognitive effects in part due to the divergent roles of astrocytes in males and females,” stated Dr. Anna Orr.
Moving forward, the lab is investigating the underlying causes of these differential effects and whether other brain functions are also altered in a sex-specific manner. This research underscores the importance of considering biological sex in neurological studies and could pave the way for more tailored and effective treatments for brain disorders.
The full study is available in the May 24 issue of Cell Reports.