MAR 14, 2018 10:30 AM PDT

Studying Sex-Specific Signaling to Understand Male Bias in Neurodevelopmental Disorders

Presented at: Neuroscience 2018
Speaker
  • Assistant Professor of Pharmacology and Physiology, and Integrative Systems Biology, GW Institute for Neuroscience
    Biography
      M. Chiara Manzini is a human geneticist and cell biologist whose laboratory focuses on the molecular mechanisms of brain development. Her group at the George Washington University, identified disease-causing mutations in families affected by brain malformations, intellectual disability and autism. She uses both zebrafish and mouse models to study the cellular function of these disease genes. She obtained her undergraduate degree in Molecular Biology from the University of Pavia in Italy, a PhD in Neurobiology and Behavior from Columbia University in New York City, and completed postdoctoral training in neurogenetics at Boston Children's Hospital/Harvard Medical School in Boston. She joined the GWU faculty in 2013.

    Abstract

    Since its initial description more than 70 years ago, autism spectrum disorder (ASD) has been diagnosed more frequently in boys. However, we remain unsure of why males are affected in greater numbers. Genetic and hormonal causes have been proposed, but clinicians and researchers are still debating whether males are more susceptible or females are more resilient. One primary hurdle in testing different hypotheses was the lack of appropriate animal models. In developing a novel mouse model of ASD and intellectual disability (ID) lacking Coiled-coil and C2 domain containing 1a, CC2D1A, which is mutated in humans with ID, ASD and seizures, we found that male mice are more severely affected than females. While males show an array of memory and sociability deficits with hyperactivity and anxiety, females only display a subset of learning impairments. In parallel, sex-specific behavioral differences correlate with male-specific reduction in activation of the transcription factor CREB in the hippocampus of KO animals. CREB function is critical for spatial memory formation, and modulation of CREB signaling rescues both molecular and behavioral deficits in male KO mice. Our results indicate that CC2D1A may establish male-specific signaling processes controlling memory. Defining how male-specific signaling is established will provide key insight on sex specific signaling in the brain, and will also lead to significant advances in the understanding of mechanisms that could lead to male bias in neurodevelopmental disorders.


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