The role of maternal infections in neurodevelopmental psychiatric disorders: focus on the P2X7/NLRP3/IL-1β signalling pathway

Abstract

Immune activation in the prenatal and early postnatal periods is increasingly implicated in the aetiology of neurodevelopmental disorders, such as autism spectrum disorder and schizophrenia, by disrupting critical neurodevelopmental processes. The impact of immune activation on brain development can be influenced by the type, timing, location, and severity of the infection. Viral, bacterial, and parasitic infections, as well as maternal autoimmune diseases, can lead to the activation of the purinergic P2X7 receptors, thereby contributing to neuroinflammation. Upon activation, P2X7 induces the assembly of the NLRP3 inflammasome, leading to the release of the pro-inflammatory cytokine IL-1β. Besides activation of additional inflammatory mediators, excessive IL-1β during critical periods of brain development can disrupt neuronal migration, synapse formation, dendritic morphology and blood-brain barrier integrity, contributing to a range of neurodevelopmental abnormalities. Animal studies have shown that inhibiting the components of the P2X7/NLRP3/IL-1β pathway can mitigate these adverse effects. This review examines the role of the P2X7/NLRP3/IL-1β pathway in mediating the effects of infection and neuronal inflammation on brain development. We discuss the therapeutic potential of targeting this pathway with a balanced approach that reduces long-term neuronal inflammation while preserving essential immune functions.

Keywords: Interleukin-1β; Maternal immune activation; NLRP3; Neurodevelopment; Neurodevelopmental disorders; P2X7; Prenatal infection.

Fig. 1

Activation of the P2X7/NLRP3/IL-1β signalling pathway in MIA animal models. TLR3 recognises double-stranded RNA, such as poly(I:C), leading to NF-κB-dependent upregulation of inflammatory cytokine precursors and NLRP3 components. Increased extracellular ATP then activates P2X7, resulting in the formation of NLRP3 inflammasome. This complex activates caspase-1 via dimerisation and self-cleavage. Active caspase-1 processes pro-IL-1β into its biologically active form by proteolysis, ready to be released into the extracellular space

Fig. 2

Critical periods of vulnerability of the developing nervous system to maternal immune activation. A comparative overview of the timing of neurodevelopmental processes and vulnerability tomaternal immune activation across human, rat, and mouse models. The developing nervous system, including that of the human fetus, exhibits varying vulnerability to maternal immune activation throughout gestation. First-trimester infections are associated with a higher risk of schizophrenia, while second-trimester infections are linked to an increased risk of ASD. Third trimester infections show a slight association with increased ASD risk. The timelines of key developmental processes (e.g., neurogenesis, gliogenesis, synaptogenesis) are aligned across species to highlight translationally relevant windows. The expression of P2X7, starting at E14-15in the rat brain and continuing through postnatal development, and the high prenatal andpostnatal expression of IL-1β (detectable from E14, peaking at E18, and declining to low adult levels), suggest their crucial roles in brain development during these vulnerable periods. Maternal immune activation during these stages could disrupt these critical processes, potentially contributing to neurodevelopmental disorders.