Weill Cornell Medicine scientists have discovered that astrocyte receptors can have opposite effects on cognitive function in male and female preclinical models. Published in Cell Reports, the study reveals that astrocytes play a crucial role in sex-specific brain mechanisms. Focusing on the mGluR3 receptor, the research demonstrated that increasing its levels enhanced memory in older females while reducing it impaired memory in young females. Conversely, in males, reducing mGluR3 enhanced memory. These findings suggest that therapeutics targeting astrocytic receptors may need to be evaluated for sex-specific effects, highlighting the importance of considering biological sex in neurological research.
Research from Weill Cornell Medicine reveals that astrocyte receptors impact cognitive functions differently in males and females, suggesting a need for sex-specific approaches in developing treatments targeting these brain cells.
Scientists at Weill Cornell Medicine have discovered the first evidence that receptors in astrocytes, brain cells that support and regulate neurons, can have contrasting effects on cognitive function in male and female preclinical models. This research highlights the role of astrocytes in contributing to gender-specific brain mechanisms.
While many studies have tested the behavioral effects of astrocytic receptors, none of them have addressed whether biological sex plays a role and most have tested only males. This study, published on May 24 in 
This image of the mouse hippocampus, a part of the brain involved in learning and memory, shows mGluR3 receptors on astrocytes (green), neurons (red), and cell nuclei (blue). Credit: Orr Lab
To understand if these divergent effects were unique to mGluR3 or reflected a broader feature of astrocytic receptor signaling, Dr. Meadows worked with co-author Dr. Adam L. Orr, an assistant professor of research in neuroscience in the Brain and Mind Research Institute and the Appel Alzheimer’s Disease Research Institute, to selectively stimulate different astrocytic receptors while mice performed tasks involving learning and memory.
To their surprise, 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,” Dr. Adam Orr said.
This study suggests that mGluR3 modulators being developed for treating disorders such as schizophrenia and anxiety may need further study to assess their impact on different sexes. “Therapeutics influencing astrocytic receptors may cause sex-specific cognitive effects in part due to the divergent roles of astrocytes in males and females,” said Dr. Anna Orr.
The lab is investigating what may cause the differential effects and if other brain functions are also changed in a sex-specific way.
Reference: “Hippocampal astrocytes induce sex-dimorphic effects on memory” by Samantha M. Meadows, Fernando Palaguachi, Minwoo Wendy Jang, Avital Licht-Murava, Daniel Barnett, Till S. Zimmer, Constance Zhou, Samantha R. McDonough, Adam L. Orr and Anna G. Orr, 24 May 2024, Cell Reports.
DOI: 10.1016/j.celrep.2024.114278
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