Hippocampal astrocytes induce sex-dimorphic effects on memory
Samantha M. Meadows,
Fernando Palaguachi,
Minwoo Wendy Jang,
Avital Licht-Murava,
Daniel Barnett,
Till S. Zimmer,
Constance Zhou,
Samantha R. McDonough,
Adam L. Orr,
Anna G. Orr
Affiliations
Samantha M. Meadows
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10021, USA
Fernando Palaguachi
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
Minwoo Wendy Jang
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
Avital Licht-Murava
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
Daniel Barnett
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10021, USA
Till S. Zimmer
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
Constance Zhou
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10021, USA
Samantha R. McDonough
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10021, USA
Adam L. Orr
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10021, USA
Anna G. Orr
Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10021, USA; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10021, USA; Corresponding author
Summary: Astrocytic receptors influence cognitive function and can promote behavioral deficits in disease. These effects may vary based on variables such as biological sex, but it is not known if the effects of astrocytic receptors are dependent on sex. We leveraged in vivo gene editing and chemogenetics to examine the roles of astrocytic receptors in spatial memory and other processes. We show that reductions in metabotropic glutamate receptor 3 (mGluR3), the main astrocytic glutamate receptor in adults, impair memory in females but enhance memory in males. Similarly, increases in astrocytic mGluR3 levels have sex-dependent effects and enhance memory in females. mGluR3 manipulations also alter spatial search strategies during recall in a sex-specific manner. In addition, acute chemogenetic stimulation of Gi/o-coupled or Gs-coupled receptors in hippocampal astrocytes induces bidirectional and sex-dimorphic effects on memory. Thus, astrocytes are sex-dependent modulators of cognitive function and may promote sex differences in aging and disease.
