טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentDabbah Assadi Fadwa
SubjectMolecular and Behavioral Characterization of Neuregulin-ErbB
Signaling in Maternal Immune Activation Model and
its Involvement in Therapeutic
Strategies of ...
DepartmentDepartment of Medicine
Supervisors Professor Ron Beloosesky
Dr. Alon Shamir
Full Thesis textFull thesis text - English Version


Abstract

Dysregulation of the immune mechanisms during the course of pregnancy leads to the pathogenesis of preterm birth (birth before 37 weeks of gestation). That affects brain development and have long-term effects on behavior and cognition. Worldwide, a common clinical practice of Magnesium sulfate (MgSO4) therapy as a neuroprotector to woman at high risk of imminent preterm birth is widely used nowadays.

In this study we explore the neuregulin (NRG1)-ErbB4 signaling as it plays a critical role in normal embryonic brain development, in the biology of Dopaminergic, GABAergic and Glutamatergic systems. Therefore, we hypothesize that this pathway may be involved with the maternal immune insult long lasting effect and also in the neuroprotection role of MgSO4. We show that MIA at late, but not at early gestation day altered the expression of NRG1, its receptor ErbB4 and the dopamine D2 receptor four hours post injection of viral or bacterial mimic infection. This suggests the acute impact of MIA on the expression of the NRG1-ErbB signaling in the premature brain of the MIA embryos 4 hours post exposure. In long term behavioral aspect, we demonstrate that poly IC exposure at late stages of the pregnancy results in a gender-dependent long term behavioral dysfunction. Adult Female-exposed, and not juvenile, display hyperlocomotion activity and lack preference to a novel object in adulthood. While working memory alteration observed only in an adult male.

Molecularly, we show for the first time that short-term treatment with MgSO4 affects the fetal brain expression of NRG1, NRG3, GAD67, tyrosine hydroxylase (TH), dopamine D2, and D1 receptors, GluN1, and GluN2B. More specifically, the data suggest that the NRG-ErbB, GAD67, TH, D2R, and NMDA signaling are possibly involved in the estimated neuromodulation mechanism of MgSO4 at early gestation day. MgSO4 exposure under inflammation at late stage of pregnancy resulted in a gender dependent behavioral dysfunction at adulthood. Adult females who were exposed to LPS/Mg display less preference to novel objects. While in juvenile we detect normal behavior. Besides, at juvenile, we detect a significant reduction in time spent in the center of the open field in both females and males in Mg treated groups. Molecularly, we detect a major effect of Mg treated groups (Mg and Mg/LPS) by downregulating the IL6 expression in HC and PFC as compared to saline and LPS treated groups. Also in D2DR expression, in PFC we observe a further similar Mg effect as compared to saline treatment, and as compared to LPS group. NRG1 and ErbB4 expression was not effected in MG treated groups as compared saline oppositely from LPS group which we detect upregulations in LPS samples (in PFC) which was preserved from fetal stage.


 Based on the abovementioned, the significance of this study is in its potential to advance the presently under-investigated healing mechanism for clinically important neuroprotective role of magnesium sulfate A deeper understanding of pivotal pathways in brain injury is essential and needed for the development of efficacious strategies for neuroprotection and prevention of long term brain injury to the offspring.