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

Abstract

Aims: Prenatal 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. Methods: We 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. Results: Poly 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. Conclusion: Our study confirms previous evidence that females are less susceptible to MIA and highlights PPARα as a potential target for treatments in schizophrenia.