Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors

Abstract

With the umbrella term 'neurodevelopmental disorders' (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary for the proper development of fetal brain cytoarchitecture and functionality. In recent years, several genetic disorders caused by mutations in key enzymes involved in purine metabolism have been associated with autism-like behavioral outcomes. Further analysis revealed dysregulated purine and pyrimidine levels in the biofluids of subjects with other NDDs. Moreover, the pharmacological blockade of specific purinergic pathways reversed the cognitive and behavioral defects caused by maternal immune activation, a validated and now extensively used rodent model for NDDs. Furthermore, Fragile X and Rett syndrome transgenic animal models as well as models of premature birth, have been successfully utilized to investigate purinergic signaling as a potential pharmacological target for these diseases. In this review, we examine results on the role of the P2 receptor signaling in the etiopathogenesis of NDDs. On this basis, we discuss how this evidence could be exploited to develop more receptor-specific ligands for future therapeutic interventions and novel prognostic markers for the early detection of these conditions.

Keywords: P2 receptors; maternal immune activation; neurodevelopmental disorders; purinergic signaling.

Figure 1

During pregnancy, perinatal insults and maternal immune activation (MIA), together with genetic predisposition, may compromise the physiological development of fetal brains’ cytoarchitecture, which is then mirrored by impairments in the formation of neural circuitries, astrogliosis, microglia shifting from a homeostatic to a reactive state and myelin damage in the brain of affected subjects during postnatal life. These pathological alterations have also been reported to be paralleled by changes in the purine and pyrimidine metabolites profile, as detected in human biofluids of children affected by neurodevelopmental disorders (NDDs). Epidemiological studies support the theory that a state of systemic inflammation and the substantial release of proinflammatory mediators may be related to the increased levels of purines detected in patients suffering from NDDs, which may act as damage-associated molecular patterns (DAMPs) and, thereby, potentially lead to defects in the physiological development of the central nervous system (CNS).

Figure 2

Schematic representation of the P2X7-NLRP3 and TLR3 pathways of innate immune response following an inflammatory insult. Extracellular ATP derived from damaged cells activates the P2X7 purinergic receptor, resulting in a decrease in intracellular K⁺ and increase in intracellular Ca²⁺. These molecular events lead to the oligomerization of NLRP3 subunits and to the recruitment and oligomerization of the apoptosis-associated speck-like protein (ASC), which contains the caspase recruitment and activation domain (CARD), giving rise to the mature NLRP3 inflammasome. Subsequently, ASC filaments recruit pro-caspase-1 to the NLRP3 inflammasome and promote its activation into caspase-1. Concurrently, the transmembrane Toll-like receptor 3 (TLR3) senses the presence of exogenous nucleic acids or synthetic immune stimulants, such as Poly(I:C), in the extracellular environment, and, upon activation, it is internalized. TLR3 internalization leads to increased production of proinflammatory precursors, particularly pro-IL-1β and pro-IL-18, which are then cleaved by caspase-1 into their mature forms, namely, IL-1β and IL-18. Mature proinflammatory mediators are then released in the extracellular environment. An upward pointing arrow means an increase, whereas a downward pointing arrow is indicative of a decrease.

Figure 3

Exemplification scheme of the pathogenic mechanisms leading to the development of some neurodevelopmental disorders, in which a role of P2 or P2-like purinergic receptors has been observed. (A). In the Fragile X syndrome, the reduced expression of the Fmr1 gene in cultured astrocytes results in increased expression of P2Y2 and P2Y6 purinergic receptors, which, in turn, leads to augmented intracellular levels of calcium, following the application of exogenous ATP and UTP. In addition, UTP application also induces a higher secretion and expression of TSP-1 glycoprotein, which, by interacting with and activating neuronal α2δ-1 channels, promotes the establishment of a stronger excitatory signaling. On the contrary, P2Y antagonism exerted by suramin prevents intracellular calcium elevations. (B). In the MECP2 KO mice model of Rett syndrome, either the silencing of the expression of P2x7 gene, the transplantation of P2X7 KO leukocytes, or the P2X7 receptor blockade obtained from the antagonism by Brilliant Blue G, results in a decrease in inflammation, in a reduction in dendritic spine loss and in an overall improvement in psychomotor outcomes. (C). In the Ts65Dn mouse model of Down syndrome, trisomic expression of miR-155 reduces SNX27 protein expression. This was hypothesized to significantly drive GPR17 toward lysosomal degradation which, in turn, is responsible for the observed reduction in GPR17+ cells and for the altered differentiation of oligodendrocytes (OL). (D). In Williams syndrome, the aberrant hypomethylation of the Gpr17 gene downregulates its expression, impairing OL maturation, reducing the physiological axonal myelination and promoting white matter alterations, eventually leading to social and behavioral abnormalities. An upward pointing arrow means an increase, whereas a downward pointing arrow is indicative of a decrease.