Autotaxin (ATX) is a secreted lysophospholipase that is essential for normal proliferation, migration, and survival of neural stem cells (NSC) during embryonic development. Deletion of ATX is embryonic lethal explaining the lack of information regarding its role in supporting NSC proliferation during the perinatal period (postnatal days 1-21). Here we show that expression of ATX in the hippocampus (HP) peaks during the perinatal period and is dramatically decreased when mice pups are exposed to chronic or acute stress during this period. We also present preliminary data that 21-day old pups that are heterozygous for the ATX gene have reduced NSC proliferation in the dentate gyrus (DG) and a decrease in granule cell layer (GCL) volume. Based on these preliminary data we hypothesize that ATX expression in the developing HP is essential for normal DG development (aim 1), that restoring normal levels of ATX to pups exposed to early life stress (ELS) will block the inhibitory effect that ELS has on DG development (aim 2), and that ATX expression in the developing HP is rapidly regulated by corticosterone levels (aim 3). If confirmed, this work will make three important contributions to previous work. First, it will demonstrate for the first time that normal DG formation, during the perinatal period, requires high expression levels of ATX. Second, it will show that corticosterone levels in the plasma tightly regulate ATX levels in the developing HP. Third, it will provide a novel molecular mechanism to explain how exposure to stress, during the perinatal period, affects DG development. We predict that ATX plays a similar role in DG development in humans, and that this work will identify a critical pathway by which abuse and neglect early in life cause long-term dysfunction in the HP of adult humans. .

Public Health Relevance

Children exposed to abuse or neglect are more likely to develop depression, anxiety and psychotic symptoms that in many cases become chronic and refractory to treatment later in life. We identified a novel molecular pathway in the developing brain that may explain how stress early in life influences neurodevelopment in a manner that affects brain functioning throughout life. Our hope is that this work will establish new diagnostic and interventional strategies to help children that have been abused early in life.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH098181-02
Application #
8660708
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510