Abstract
SummaryAimsPrenatal maternal immune activation (MIA) is associated with a risk to develop schizophrenia and affects dopamine systems in the ventral tegmental area (VTA), key region in the neurobiology of psychoses. Considering the well‐described sex differences in schizophrenia, we investigated whether sex affects MIA impact on dopamine system and on schizophrenia‐related behavioral phenotype. Furthermore, considering peroxisome proliferator‐activated receptor‐α (PPARα) expression in the CNS as well as its anti‐inflammatory and neuroprotective properties, we tested if PPARα activation by prenatal treatment with a clinically available fibrate (fenofibrate) may mitigate MIA‐related effects.MethodsWe induced MIA in rat dams with polyriboinosinic‐polyribocytidylic acid (Poly I:C) and assessed prepulse inhibition and dopamine neuron activity in the VTA by means of electrophysiological recordings in male and female preweaned and adult offspring.ResultsPoly I:C‐treated males displayed prepulse inhibition deficits, reduced number and firing rate of VTA dopamine neurons, and paired‐pulse facilitation of inhibitory and excitatory synapses. Prenatal fenofibrate administration attenuated detrimental effects induced by MIA on both the schizophrenia‐like behavioral phenotype and dopamine transmission in male offspring.ConclusionOur study confirms previous evidence that females are less susceptible to MIA and highlights PPARα as a potential target for treatments in schizophrenia.
Highlights
Environmental factors, such as prenatal infections, can lead to ab‐ errant brain development, emerging in pathological phenotypes
In order to test the hypothesis of sex differences in the outcome of maternal immune activation (MIA), we designed this investigation as a follow‐up of our previous study, whereby, consistent with previous literature, we found that male offspring from polyribocytidylic acid (Poly I):C‐treated dams show marked deficits in prepulse in‐ hibition 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 ventral tegmental area (VTA) dopamine neurons.[18]
Nigrostriatal dopamine trans‐ mission 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 me‐ solimbic dopamine pathway, and chose to analyze PPI, a behavior that is dependent on mesolimbic dopamine, as an index of psy‐ chotic‐like behavioral abnormalities
Summary
Environmental factors, such as prenatal infections, can lead to ab‐ errant brain development, emerging in pathological phenotypes. Prenatal exposure to polyriboinosinic‐polyribocytidylic acid (Poly I:C), a double‐stranded synthetic RNA that triggers an innate immune response, induces MIA in rodents by mimicking a viral. |2 infection and has been shown to induce schizophrenia‐like pheno‐ types in rodents.[2] These phenotypes display behavioral abnormali‐ ties, including sensorimotor gating impairment as well as alterations in brain regions key in the neuropathology of psychoses, such as do‐ paminergic ventral tegmental area (VTA) or prefrontal cortex. Dysregulation of dopamine transmission in the striatum, es‐ pecially in the rostral caudate, is considered an additional hallmark of schizophrenia.[3,7]
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