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

• Published in: CNS neuroscience & therapeutics 2019-05, Vol.25 (5), p.549-561
• Main Authors: De Felice, Marta, Melis, Miriam, Aroni, Sonia, Muntoni, Anna Lisa, Fanni, Silvia, Frau, Roberto, Devoto, Paola, Pistis, Marco
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Dopamine; Dopamine - metabolism; dopamine neurons; electrophysiology; Female; Fenofibrate; Fenofibrate - pharmacology; Firing rate; Gender differences; Immune response; Inflammation; Male; maternal immune activation; Mental disorders; Nervous system; Neuroimmunomodulation; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neurosciences; Offspring; Original; peroxisome proliferator‐activated receptor‐alpha; Phenotypes; Poly I-C; Polyinosinic:polycytidylic acid; PPAR alpha - agonists; Pregnancy; Pregnancy Complications - drug therapy; Pregnancy Complications - immunology; Prenatal Exposure Delayed Effects - prevention & control; Protective Agents - pharmacology; Psychosis; Random Allocation; Rats, Sprague-Dawley; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - immunology; Sex differences; Synapses; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - metabolism; Ventral tegmentum
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13087

Summary 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.