Purinergic signaling is involved in many neurodevelopmental alterations that eventually lead to severe disorders, such as autism spectrum disorders (ASD). It was suggested that metabolic pathways that synthesize and catabolize purines are critical regulatory elements in ASD and play a role in promoting behavioral abnormalities. However, the molecular basis of the altered purine metabolism in autism still remains to be elucidated. AIM(S): Investigation the effect of embryological exposure to valproic acid (VPA) – rodent model of environmentally triggered autism – on extracellular nucleotides level and turnover as well as the expression and activity of selected purinergic receptors in the brain cortex of adolescent rats. METHOD(S): Pregnant Wistar rats received a single i.p. injection of VPA (450 mg/kg b.w.) on gestational day 12.5. We isolated CSF and brain cortex from the adolescent (52‑day‑old) male offspring. The experiments were also conducted on primary neuronal cultures isolated from VPA rat pups on the 19th embryonic day. RESULTS: Prenatal exposure to VPA significantly elevated ATP, ADP, and AMP levels in the CSF of adolescent animals, whereas the level of adenosine was unchanged. Concomitantly, cortical expression of ATP hydrolyzing enzymes was significantly decreased. Prenatal exposure to VPA also generated a rearrangement of selected ionotropic and metabotropic purinergic receptors. While the level of purinergic P2X7 and P2Y1 receptors was decreased, the expression of P2X1 receptor was elevated. Additionally, we observed hyperactivity of purinergic receptors in primary neurons isolated from VPA animals. Stimulation of these cells with 1mM ATP induced a 4‑fold increase in intracellular calcium level as compared to control cells. CONCLUSIONS: Prenatal exposure to VPA induces purinergic signaling deregulation in the brain cortex of adolescent offspring and may be involved in the behavioral deficits in ASD. FINANCIAL SUPPORT: Supported by NSC grant 2017/25/B/NZ4/01969.
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