Maternal immune activation impairs endocannabinoid signaling in the mesolimbic system of adolescent offspring

Introduction Maternal infections during pregnancy could harm the progeny and, when combined with postnatal insults, increase the risks of developing psychiatric disorders such as schizophrenia. The two-hit hypothesis of schizophrenia postulated that maternal immune activation (MIA) could act as a first and, later on in life, a second hit (e.g. stress or drug of abuse) could exacerbate latent abnormalities. Thus, we previously tested in a MIA model of schizophrenia whether a second hit during adolescence could exacerbate the dysfunctions observed in adult offspring. For this purpose, we treated adolescent rats with Δ9-Tetrahydrocannabinol (THC), the main psychoactive compound in cannabis. Unexpectedly, THC did not exacerbate the dysfunctions observed in adult rats but attenuated them. These results prompted us to focus on the complex interplay between the endocannabinoid and the dopamine systems and their entangled neurodevelopmental trajectories in a MIA model. Aim This study aimed to investigate the hypothesis that MIA affects the endocannabinoid system and the endocannabinoid-mediated modulation of dopamine functions. Rats were tested during adolescence to assess (i) the behavioral endophenoype evaluated by locomotor activity in response to THC and prepulse inhibition of startle reflex, (ii) the properties of ventral tegmental area (VTA) dopamine neurons in vivo and their response to cumulative doses of THC, (iii) the endocannabinoid-mediated synaptic plasticity in VTA dopamine neurons, (iiii) the expression of cannabinoid receptors and enzymes involved in endocannabinoid synthesis and catabolism in mesolimbic structures. Methods We used a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid (Poly I:C). Dopamine cell activity in the VTA was studied by performing extracellular recordings in anesthetized male rats and whole-cell patch clamp recordings in slices. We also measured the expression of cannabinoid receptors and enzymes in the nucleus accumbens (NAc) and midbrain by performing western blot analysis. Results Dopamine neurons recorded from Poly I:C rats displayed a higher percentage of spikes in burst than controls. Cumulative doses of THC produced a dose-dependent decrease in the firing rate of VTA dopamine neurons in control rats but were ineffective in Poly I:C rats. Consistently, Poly I:C offspring displayed a larger 2-arachidonoylglycerol (2-AG)-mediated depolarization-induced suppression of inhibition (DSI) than controls. The larger DSI in Poly I:C rats was not due to differences in CB1 number or function but to a reduced 2-AG degradation. Coherently, Poly I:C rats showed a decreased level of monoacylglycerol lipase (MAGL), the enzyme that hydrolyzes 2-AG, both in the NAc and midbrain. Conclusions We conclude that MIA enhanced endocannabinoid-mediated synaptic plasticity can be ascribed to enhanced 2-AG signaling and decreased activity of MAGL in mesolimbic structures. This might change the balance between excitatory and inhibitory inputs to VTA dopamine cells and impair their firing activity. These results confirm that MIA perturbs the complex interplay between dopamine and endocannabinoid systems during adolescence and might generate a pathological endophenotype that leads to psychotic-like symptoms later in life.