Targeting the P2X7 receptor signaling pathway: Unlocking therapeutic strategies for autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a common developmental neurological disorder that has a significant genetic predisposition and is marked by an early beginning of impairment of social communication and restricted repetitive behaviors, as well as loss of interest in activities. Though it is a common condition, pathogenetic mechanisms and etiologic foundations are still unclear; diagnostic strategies and treatments remain inadequate and restricted. Hence, there is an ongoing need to develop safer and more effective therapeutic strategies. Recent findings indicate P2X7 receptor upregulation plays a key role in ASD development through multiple pathological mechanisms, including maternal immune activation, mitochondrial dysfunctioning, oxidative stress, and neuroinflammation. When ATP from outside the cell attaches to P2X7 receptors, it opens channels that let sodium, calcium, and potassium flow in and out of the cell. Long-term receptor stimulation generates large pores in the membrane, potentially facilitating apoptotic and inflammatory mechanisms. So, based on studies using drugs that block the P2X7 receptor and genetic methods, stopping the P2X7 receptor appears to improve the harmful effects related to ASD. So, the therapeutic lead is the brain-permeable P2X7 receptor antagonists that deserve more complete clinical validation. This review discusses how the P2X7 receptor is involved in the development of ASD and looks at possible drug strategies to slow down the disease.

Keywords: Autism spectrum disorder; Maternal immune activation; Mitochondrial dysfunctioning; Neuroinflammation; Oxidative stress; P2X7 receptor.

Fig. 1

Underlying factors contributing to autism spectrum disorder. ∗Genetic factors related to ASD include mutation in Activity-Dependent Neuroprotective Protein (ADNP), chromodomain helicase DNA-binding proteins 2 and 8 (CHD2, CHD8), and Phosphatase and Tensin Homolog (PTEN). Environmental factors consist of prenatal and postnatal factors that contribute to the activation of the mother's immune system, gestational diabetes, and parental age, which plays an important role in the etiology of ASD.

Fig. 2

Activation of P2X7 receptor. The P2X7 receptor is an ATP-gated ion channel receptor. When ATP binds, it triggers conformational changes that lead to the opening of a cation-selective pore.

Fig. 3

P2X7 receptor mediated maternal immune activation. Activation of the P2X7 receptor by extracellular ATP leads to activation of the maternal immune system, which increases the production of inflammatory cytokines. These cytokines cross the placental barrier and enter fetal circulation. In the fetal brain, this immune activation stimulates microglial cells, leading to increased inflammatory mediators, neuroinflammation, and subsequent neural dysfunction. This cascade of neuroinflammatory events during fetal development may contribute to autism-like phenotypes in offspring.

Fig. 4

P2X7 receptor mediated neuroinflammation in fetal brain. ∗FADD: Fas-associated death domain protein; NEK7: NIMA-related kinase 7; ASC: Apoptosis-associated Speck-like protein; TLR: Toll like receptor; GSDMD: Gasdermin D; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B cells.