Transgenerational Sex-dependent Disruption of Dopamine Function Induced by Maternal Immune Activation.

Michele Santoni,Marco Pistis,Roberto Frau

doi:10.3389/fphar.2022.821498

Abstract

Several epidemiological studies suggest an association between maternal infections during pregnancy and the emergence of neurodevelopmental disorders in the offspring, such as autism and schizophrenia. Animal models broadened the knowledge about the pathophysiological mechanisms that develop from prenatal infection to the onset of psychopathological phenotype. Mounting evidence supports the hypothesis that detrimental effects of maternal immune activation might be transmitted across generations. Here, we explored the transgenerational effects on the dopamine system of a maternal immune activation model based on the viral mimetic polyriboinosinic-polyribocytidilic acid. We assessed dopamine neurons activity in the ventral tegmental area by in vivo electrophysiology. Furthermore, we studied two behavioral tests strictly modulated by the mesolimbic dopamine system, i.e., the open field in response to amphetamine and the prepulse inhibition of the startle reflex in response to the D2 agonist apomorphine. Second-generation adult male rats did not display any deficit in sensorimotor gating; however, they displayed an altered activity of ventral tegmental area dopamine neurons, indexed by a reduced spontaneous firing rate and a heightened motor activation in response to amphetamine administration in the open field. On the other hand, second-generation female rats were protected from ancestors’ polyriboinosinic-polyribocytidilic acid treatment, as they did not show any alteration in dopamine cell activity or in behavioral tests. These results confirm that maternal immune activation negatively influences, in a sex-dependent manner, neurodevelopmental trajectories of the dopamine system across generations.

Highlights

A wealth of evidence suggests that exposure to environmental factors during pregnancy increases the risk of developing neuropsychiatric diseases in the offspring
We previously demonstrated that maternal immune activation (MIA) impacts electrophysiological properties of midbrain dopamine neurons in F1 male, but not female, offspring (De Felice et al, 2019; Lecca et al, 2019)
We carried out in-vivo single-unit extracellular recordings of ventral tegmental area (VTA) dopamine neurons in anesthetized F2 male and female rats to determine whether MIA transgenerationally induced sex-dependent effects on the spontaneous activity of dopamine cells

Summary

Introduction

A wealth of evidence suggests that exposure to environmental factors during pregnancy increases the risk of developing neuropsychiatric diseases in the offspring. MIA rats exhibit heightened susceptibility to the effects of the psychotomimetic drugs amphetamine and phencyclidine, which are known to elicit positive, negative, and cognitive schizophrenia-like symptoms in healthy humans and laboratory animals (Meyer et al, 2006; Ozawa et al, 2006) These psychotic-like phenotypes are especially underpinned by alterations in the mesolimbic dopamine system, whose abnormalities are considered a final common mechanism in the neuropathogenesis of schizophrenia (Meyer et al, 2008a; Vuillermot et al, 2010). We reported a marked change of VTA dopamine neuron activity and a higher dopamine release in the NAc (Luchicchi et al, 2016; De Felice et al, 2019; Lecca et al, 2019) Of note, it has been recently demonstrated the involvement of MIA effects in the first descendants and across generations suggesting a transgenerational transmission (Weber-Stadlbauer et al, 2017; Weber-Stadlbauer et al, 2021). To better detect the activity of the mesolimbic dopamine function, we assessed dopamine neuron activity by in vivo electrophysiology

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