Prenatal restraint stress induces a pre-parkinsonian phenotype

Orateur : Stefania MACCARI (PhD, Professor in Neuroscience Neural Plasticity Team - UMR 8576 CNRS/USTL, Structural and Functional Glycobiology Unit, North University of Lille, France)

Suspect events in early life including stress, poor nutrition, infections, and environmental factors such as chemical and pesticide exposure may contribute to late-life neurodegenerative disease development like Parkinson’s disease. In humans, Parkinson disease is associated to a dysfunction of developing dopaminergic system. Evidences provided by animal research, as well as retrospective studies in humans, pointed out that exposure to adverse events in early life can alter adult behaviors and neurochemical indicators of midbrain DA activity, suggesting that the development of the DA system is sensitive to disruption by exposure to early stressors. Prenatal restraint stress (PRS) in rats is a well-characterized animal model to study neuroadaptive changes in adulthood in response to an insult in early life. PRS rats exhibit an anxious/depressive-like profile that likely reflects the development of a pathological epigenetic programming. We used adult rats subjected to PRS to examine the impact of early life stress on the function of the basal ganglia motor circuit in the adult life. Male adult PRS rats showed a number of impairments in striatal performance tests like active avoidance, grip strength and pasta matrix reaching task. PRS markedly reduced depolarization-evoked 3H-dopamine release in superfused striatal synaptosomes, with no changes in 3H-noradrenaline, glutamate and GABA release in the striatal synaptosomes, and 3H-dopamine release in hippocampal and cortical synaptosomes. We also found an increase in striatal levels of dopamine, DOPAC, and homovanillic acid. Accordingly, PRS increased tyrosine hydroxylase protein level in striatum. Conversely, no changes were detected for dopamine receptors D1 and D2 or the transporter DAT, neither for F-DOPA uptake from dopamine fibers. In addition, striatal projection neurons of PRS rats did not show changes in resting membrane potential, in AMPA/NMDA ratio-mediated inward currents, and in LTD of excitatory synaptic transmission in response to high frequency stimulation of the cortico-striatal pathway. PRS also show an increase in A2A adenosine receptor activity and mRNA level in striatum while the activity of mGluR5 receptors was unaffected. Transcript level of pro-dynorphin in striatum was also increased in PRS rats. Taken together our results show that changes within dorsal striatum in PRS rats are consistent with a latent parkinsonian-like state, raising the hypothesis that vulnerability to ageing disorders can be programmed by stressful events in early life.

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