EFFECTS OF PPAR-ALPHA ACTIVATION IN AN IMMUNE-MEDIATED NEURODEVELOPMENTAL MODEL OF SCHIZOPHRENIA

Maternal immune system activation (MIA) at specific ages of pregnancy is considered a prenatal risk for psychiatric disorders with a neurodevelopmental origin, including schizophrenia. Gender, age and genetic background can also interact with the outcome of the illness. Furthermore, a role of ventral tegmental area (VTA) dopamine neurons in the pathophysiology has been established. Currently, pharmacological strategies to reduce the risk of neurodevelopmental disorders are lacking. The role of peroxisome proliferator-activated receptors-alpha (PPARα), a member of a nuclear receptors family widely expressed in the CNS, is attracting a special interest. Activation of PPARα has been found to regulate gene expression involved in inflammation and neuroprotection. Here, we examined how dopamine activity was impacted by MIA and whether gender moderates this impact. Subsequently, we investigated if PPARα activation prevents neurodevelopmental MIA-related disturbances. To mimic a viral infection, dams were injected at gestational day (GD) 15, comparable to the second trimester of human pregnancy, with the proinflammatory cytokine inductor polyriboinosinic-polyribocytidilic acid [Poly I:C, 4 mg/kg i.v.] or vehicle. Animals were fed from GD 8 to GD 18 with either a standard diet or fenofibrate-containing diet (0.2% w/w). Fenofibrate is a clinically approved PPARα agonist used as lipid-lowering medication. Prepulse inhibition (PPI) of acoustic startle reflex and in vivo single unit extracellular recordings of VTA dopamine cells were performed in adult offspring. Considerable gender differences were detected in all parameters examined. Male but not female offspring of Poly I:C-exposed dams displayed impairments in PPI when compared to controls. Similarly, dopamine activity was disrupted by Poly I:C treatment exclusively in males, resulting in a reduction in the number of spontaneously active dopamine cells, in their frequency and bursting activity. These effects were prevented by fenofibrate treatment. Our study demonstrates a gender-dependent effect of MIA on behavior and dopamine transmission and highlights a protective effect of PPARα agonists