Alterations of Purinergic Receptors Levels and Their Involvement in the Glial Cell Morphology in a Pre-Clinical Model of Autism Spectrum Disorders

Abstract

Recent data suggest that defects in purinergic signalling are a common denominator of autism spectrum disorders (ASDs), though nothing is known about whether the disorder-related imbalance occurs at the receptor level. In this study, we investigated whether prenatal exposure to valproic acid (VPA) induces changes in purinergic receptor expression in adolescence and whether it corresponds to glial cell activation. Pregnant dams were subjected to an intraperitoneal injection of VPA at embryonic day 12.5. In the hippocampi of adolescent male VPA offspring, we observed an increase in the level of P2X1, with concomitant decreases in P2X7 and P2Y1 receptors. In contrast, in the cortex, the level of P2X1 was significantly reduced. Also, significant increases in cortical P2Y1 and P2Y12 receptors were detected. Additionally, we observed profound alterations in microglial cell numbers and morphology in the cortex of VPA animals, leading to the elevation of pro-inflammatory cytokine expression. The changes in glial cells were partially reduced via a single administration of a non-selective P2 receptor antagonist. These studies show the involvement of purinergic signalling imbalance in the modulation of brain inflammatory response induced via prenatal VPA exposure and may indicate that purinergic receptors are a novel target for pharmacological intervention in ASDs.

Correction: Babiec et al. Alterations of Purinergic Receptors Levels and Their Involvement in the Glial Cell Morphology in a Pre-Clinical Model of Autism Spectrum Disorders. Brain Sci. 2023, 13, 1088

“…In the original publication [ 1 ], there was a mistake in the legend for Scheme 1: (d) To analyse the modulation of purinergic signalling, rats at 52 PND were divided into three groups and subsequently injected with PPADS (P2X receptor antagonist), isoPPADS (250 mg/kg, i.p.) (P2 receptor antagonist), or saline.…”

Mesenchymal Stem Cells and Purinergic Signaling in Autism Spectrum Disorder: Bridging the Gap between Cell-Based Strategies and Neuro-Immune Modulation

“…P2X7R expression has been confirmed in immune cells, including monocytes, macrophages, dendritic cells, NK cells, and T and B lymphocytes, as well as in glial cells such as microglia, astroglia, and oligodendrocytes [ 72 , 73 ]—the important cells in neuroinflammatory processes occurring in neurodegenerative diseases and brain injuries [ 74 , 75 ]. The activation of P2X7 receptors triggers the activation of NLRP3 inflammasome and releases pro-inflammatory cytokines, mostly IL-1β, IL-18, IL-6, and TNF-α, as well as chemokines and growth factors [ 14 , 17 , 71 , 76 ]. Signaling via P2X7R also influences the T cells’ activation and modulates the balance between Th17 and Treg lymphocytes [ 17 ].…”

“…Signaling via P2X7R also influences the T cells’ activation and modulates the balance between Th17 and Treg lymphocytes [ 17 ]. Interestingly, P2X7R itself can trigger the release of intracellular ATP to the extracellular environment, increasing the pool of ecto-ATP [ 17 , 76 ].…”

“…The disturbances in the processes of the migration of neurons and glia, synaptogenesis, cell proliferation, and differentiation in the early stages of brain development are confirmed to be generated by abnormal signaling through purine nucleotides and nucleosides and may lead to ASD [ 76 , 126 , 127 , 128 ]. One of the triggers of purinergic alterations is prenatal exposure to VPA (valproic acid), a clinical drug used for epilepsy and mood disorders, which the intake of during pregnancy largely increases the risk of ASD in children [ 128 , 129 , 130 ].…”

“…The majority of studies on animal models of ASD confirm significant alterations in P1 and P2 receptor expression at the gene and/or protein level [ 76 , 132 ]. An interesting case was studied by Babiec and collaborators, who focused on the changes in the expression of certain purinergic receptors in rats exposed to VPA during embryonic development [ 128 ].…”