Maternal Immune Activation Disrupts Dopamine System in the Offspring

Abstract

Background:In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia.Methods:Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology.Results:Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity.Conclusions:These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.

The PPARα agonist fenofibrate attenuates disruption of dopamine function in a maternal immune activation rat model of schizophrenia

“…In our recent report, we showed that MIA ensuing Poly I:C exposure during gestation disrupts PPI in male adult rats. Here, when analyzing sex differences in the vulnerability of PPI response to MIA, we did not find an interaction between prenatal Poly I:C treatment and sex, as females showed control PPI parameters significantly different to males, and this latter might have masked any potential interaction.…”

“…Whole‐cell patch‐clamp recordings from rat VTA dopamine cells were as described previously . Extracellular single‐unit recordings from VTA DA neurons in anesthetized rats were as described previously . See Method S1 for more details.…”

“…8 Moreover, studies on the ontogeny of MIA-induced deficits showed that these are evident at PND 70. 19,20 Ex vivo electrophysiological experiments were carried out before weaning (PND [12][13][14][15][16][17][18][19][20] to the aim of detect early abnormalities in dopamine neuron activity and synaptic properties.…”

“…In order to test the hypothesis of sex differences in the outcome of MIA, we designed this investigation as a follow-up of our previous study, whereby, consistent with previous literature, we found that male offspring from Poly I:C-treated dams show marked deficits in prepulse inhibition of startle reflex (PPI) and in dopamine transmission, such as higher baseline levels of dopamine in the nucleus accumbens (NAc) and reduced number and firing rate of spontaneously active VTA dopamine neurons. 18 Although nigrostriatal dopamine transmission might be compromised in schizophrenia, in our study we focused on the VTA subregion as the vast majority of studies on animal models of schizophrenia rely on the examination of the mesolimbic dopamine pathway, and chose to analyze PPI, a behavior that is dependent on mesolimbic dopamine, as an index of psychotic-like behavioral abnormalities.…”

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts

“…There may be differences in organ response to maternal LPS administration because D 2 R not D 1 R expression is decreased in the prefrontral cortex of Sprague-Dawley rat offspring [103]. These apparent discrepancies need to be sorted out because the administration of a proinflammatory cytokine inductor, polyriboinosinic polyribocytidilic acid (poly[I:C]), during gestational day 14–16 in Sprague-Dawley rats increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex of their offspring; their ventral tegmental neurons had reduced activity but normal D 2 R autoreceptor activity [104]. …”