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

Abstract

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 .

Δ9-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation

“…The present findings confirm our previous studies that MIA, evoked by maternal exposure to Poly I:C, induces harmful effects in offspring, namely disruption of dopamine cell electrophysiological activity: (i) reduced number of spontaneously active cells; (ii) decrease in their firing rate; and (iii) profound alterations in their firing pattern (Luchicchi et al, 2016; De Felice et al, 2019). We and other groups showed that changes in dopamine transmission translate into abnormal behavior such as disrupted sensorimotor gating, deficits in cognition and social interactions (Zuckerman et al, 2003; Meyer et al, 2011; Luchicchi et al, 2016).…”

“…However, Poly I:C treatment did not affect litter size (controls: 11.6 ± 1.8 pups, n = 8; Poly I:C: 12.4 ± 1.2 pups, n = 7, P = 0.72, Student’s t -test). As our previous studies determined that detrimental effects induced by MIA were only evident in males (De Felice et al, 2019), we evaluated the effect of pubertal THC solely in male rats. Hence, prenatal Poly I:C or vehicle male offspring were randomly assigned to the adolescent THC or vehicle groups, taking care that no more than three animals from the same litter were assigned to the same experimental group or procedure (Kentner et al, 2019).…”

“…It is tempting to speculate that THC in adolescence might induce changes in CB1 receptor expression that, in our model, counteract those induced by MIA. As an example, in MIA-exposed male offspring we observed a decrease in the probability of glutamate and GABA release onto dopamine cells, indexed by an increase in the paired-pulse ratio of excitatory and inhibitory currents coupled with a reduced frequency of miniature inhibitory and excitatory postsynaptic currents (De Felice et al, 2019). As the release of GABA and glutamate is tightly regulated by 2-arachidonoylglicerol (2-AG) acting on presynaptic CB1 receptors (Melis et al, 2004, 2014), we can speculate that this reduced neurotransmitter release might be caused by an increased expression or activity of CB1 receptors on GABA or glutamate terminals, consistent with the study by Verdurand et al (2014).…”

“…Indeed, previous studies reported an increase in the number of TH-immunoreactive neurons in the VTA, TH-positive terminals in the striatum (Meyer et al, 2008; Winter et al, 2009; Vuillermot et al, 2010), increases in evoked striatal dopamine release ex vivo (Zuckerman et al, 2003) and enhanced dopamine levels in the prefrontal cortex and lateral globus pallidus (Winter et al, 2009). In our previous studies we observed a marked alteration of VTA dopamine neuron activity (reduced firing rate, reduced number of spontaneously active cells and altered firing pattern) in male but not female offspring coupled with disruption of sensorimotor gating and of cognitive and social behavior, and increase in dopamine levels in the nucleus accumbens (Luchicchi et al, 2016; De Felice et al, 2019).…”

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

“…Additionally, for its anti-inflammatory and neuroprotective properties [111], PPAR-α activation by fenofibrate prevented prenatal maternal immune activation, which in a rat model is associated with the risk of developing schizophrenia in the offspring [112]. Remarkably, prenatal administration of pioglitazone dampens the schizophrenia-like behavior observed in male offspring after prenatal maternal immune activation [112].…”