Elucidating the Role of Integrin Linked Kinase Pathway in Moderate Drinking Prenatal Alcohol Exposed Rat Model
Type of DegreeDissertation
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Alcohol and nicotine are well known teratogen which has been reported to have large scale effect on developing fetus. Prenatal alcohol cause many deleterious effect during fetal development which either persist throughout the life of an individual or may disappear as age progresses. Moderate drinking model is considered to be more appropriate model of maternal drinking in human. Time pregnant Sprague Dawley rats were used to generate moderate drinking alcohol model. Integrin Linked Kinase (ILK) is an effector of integrin and growth-factor signaling which regulates various signaling processes. In FASD, a downstream effector of ILK, Glycogen Synthase Kinase 3β (GSK3β) remains highly active (reduced Ser9 phosphorylation). GSK3β has been known to modulate glutamate receptor trafficking and channel properties. Therefore, we hypothesize that the cognitive deficits accompanying FASD are associated with impairments in the ILK signaling pathway. A significant population of women are present who drinks and smokes simultaneously during pregnancy. Thus, both of these drugs of abuse during pregnancy may have significant neurobehavioral effect on the offspring. In our study, we also investigated the effect of prenatal alcohol and nicotine co-exposure on the behavior and plasticity in adolescent rat. Another part of the study is the use of BDNF receptor TrkB agonist 7,8-DHF to ameliorate the deficiencies observed in prenatal alcohol model. We reported deficits in contextual fear conditioning behavior, spatial memory and synaptic plasticity in FASD rat model. Prenatal co-exposure to nicotine ameliorate the behavioral deficits, although failed to improve synaptic plasticity. The major finding from this study was the reduced ILK activity, interaction to calcium impermeable GluR2 AMPA receptor and increased synaptic expression of GluR2. The net effect of this has been correlated to synaptic plasticity impairment in the model. Prenatal nicotine also showed increased synaptic expression of GluR2 and therefore reduced plasticity. The neurotrophic growth factor BDNF is also deficient in the model which can reduce the ILK activity. 7,8-DHF can potentially enhance ILK activity through PI3kinase protein. Indeed, 7,8-DHF showed promising result in improvement of behavior in the model with reduced GluR2 at the synapse. This shows that plasticity can be improved using TrkB agonist in the model.