Prenatal infections can increase the risk of developing psychiatric disorders such as schizophrenia in the offspring, especially when combined with other postnatal insults. Here, we tested, in a rat model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid, whether maternal immune activation (MIA) affects the endocannabinoid system and endocannabinoid-mediated modulation of dopamine functions. Experiments were performed during adolescence to assess i) the behavioral endophenotype (locomotor activity, plus maze, prepulse inhibition of startle reflex); ii) the locomotor activity in response to Δ9-Tetrahydrocannabinol (THC) and iii) the properties of ventral tegmental area (VTA) dopamine neurons in vivo and their response to THC; iv) endocannabinoid-mediated synaptic plasticity in VTA dopamine neurons; v) the expression of cannabinoid receptors and enzymes involved in endocannabinoid synthesis and catabolism in mesolimbic structures and vi) MIA-induced neuroinflammatory scenario evaluated by measurements of levels of cytokine and neuroinflammation markers. We revealed that MIA offspring displayed an altered locomotor activity in response to THC, a higher bursting activity of VTA dopamine neurons and a lack of response to cumulative doses of THC. Consistently, MIA adolescence offspring showed an enhanced 2-arachidonoylglycerol-mediated synaptic plasticity and decreased monoacylglycerol lipase activity in mesolimbic structures. Moreover, they displayed a higher expression of cyclooxygenase 2 (COX-2) and ionized calcium-binding adaptor molecule 1 (IBA-1), associated with latent inflammation and persistent microglia activity. In conclusion, we unveiled neurobiological mechanisms whereby inflammation caused by MIA influences the proper development of endocannabinoid signaling that negatively impacts the dopamine system, eventually leading to psychotic-like symptoms in adulthood.

Parkinson’s disease (PD) is a complex pathology causing a plethora of non-motor symptoms besides classical motor impairments, including cognitive disturbances. Recent studies in the PD human brain have reported microgliosis in limbic and neocortical structures, suggesting a role for neuroinflammation in the development of cognitive decline. Yet, the mechanism underlying the cognitive pathology is under investigated, mainly for the lack of a valid preclinical neuropathological model reproducing the disease’s motor and non-motor aspects. Here, we show that the bilateral intracerebral infusion of pre-formed human alpha synuclein oligomers (H-αSynOs) within the substantia nigra pars compacta (SNpc) offers a valid model for studying the cognitive symptoms of PD, which adds to the classical motor aspects previously described in the same model. Indeed, H-αSynOs-infused rats displayed memory deficits in the two-trial recognition task in a Y maze and the novel object recognition (NOR) test performed three months after the oligomer infusion. In the anterior cingulate cortex (ACC) of H-αSynOs-infused rats the in vivo electrophysiological activity was altered and the expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) and the AMPA receptor subunit GluR1 were decreased. The histological analysis of the brain of cognitively impaired rats showed a neuroinflammatory response in cognition-related regions such as the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. We found an increased GFAP reactivity and the acquisition of a proinflammatory phenotype by microglia, as indicated by the increased levels of microglial Tumor Necrosis Factor alpha (TNF-α) as compared to vehicle-infused rats. Moreover, diffused deposits of phospho-alpha synuclein (p-αSyn) and Lewy neurite-like aggregates were found in the SNpc and striatum, suggesting the spreading of toxic protein within anatomically interconnected areas. Altogether, we present a neuropathological rat model of PD that is relevant for the study of cognitive dysfunction featuring the disease. The intranigral infusion of toxic oligomeric species of alpha-synuclein (α-Syn) induced spreading and neuroinflammation in distant cognition-relevant regions, which may drive the altered neuronal activity underlying cognitive deficits.

Maternal immune activation (MIA) during pregnancy may increase the risk for neurodevelopmental disorders such as schizophrenia and autism in offspring. Preclinical and human evidence support a potential role for MIA in the development of depressive symptoms in offspring. Among animal models of MIA, prenatal treatment with the synthetic viral mimetic polyinosinic-polycytidylic acid [poly (I:C)] is well established in studying psychotic-like and autism-like phenotypes, while its validity for modeling depressive-like behaviors remains underexplored. In this study, we assessed whether MIA, induced in rats with an injection of high molecular weight (HMW) poly (I:C), at gestational day 15, leads to a depressive-like phenotype in the offspring. In male and female offspring during adolescence and adulthood, we evaluated i) behavioral despair and anhedonia using the forced swim test (FST) and sucrose preference test (SPT); ii) the electrophysiological properties of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in vivo; iii) serum cytokine profile. We found that MIA offspring exhibited increased immobility and reduced climbing and swimming in the FST, with more pronounced effects in males, while sucrose preference remained unaltered. In vivo recordings revealed a significant increase in 5-HT neuron firing rate in MIA adult males. Peripheral cytokine analysis showed elevated IL-1α in MIA males and decreased GRO/KC levels in MIA females. In conclusion, these findings indicate that prenatal exposure to HMW poly (I:C) selectively affects stress-coping mechanisms without inducing anhedonia, modulates serotonergic signaling in a sex- dependent manner in the absence of widespread inflammatory alterations.

Maternal immune activation (MIA) during pregnancy may increase the risk for neurodevelopmental disorders such as schizophrenia and autism in offspring. Preclinical and human evidence support a potential role for MIA in the development of depressive symptoms in offspring. Among animal models of MIA, prenatal treatment with the synthetic viral mimetic polyinosinic-polycytidylic acid [poly (I:C)] is well established in studying psychotic-like and autism-like phenotypes, while its validity for modeling depressive-like behaviors remains underexplored. In this study, we assessed whether MIA, induced in rats with an injection of high molecular weight (HMW) poly (I:C), at gestational day 15, leads to a depressive-like phenotype in the offspring. In male and female offspring during adolescence and adulthood, we evaluated i) behavioral despair and anhedonia using the forced swim test (FST) and sucrose preference test (SPT); ii) the electrophysiological properties of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in vivo ; iii) serum cytokine profile. We found that MIA offspring exhibited increased immobility and reduced climbing and swimming in the FST, with more pronounced effects in males, while sucrose preference remained unaltered. In vivo recordings revealed a significant increase in 5-HT neuron firing rate in MIA adult males. Peripheral cytokine analysis showed elevated IL-1α in MIA males and decreased GRO/KC levels in MIA females. In conclusion, these findings indicate that prenatal exposure to HMW poly (I:C) selectively affects stress-coping mechanisms without inducing anhedonia, modulates serotonergic signaling in a sex- dependent manner in the absence of widespread inflammatory alterations.

Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor‐α (PPARα), with the clinically available agonist fenofibrate, attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 hours after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/CTRL group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1 levels were lower than in veh/CTRL group. Notably, MIP-1, TNF-, GRO/KC, GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, indicating the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate the consequences of MIA.