Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders

Abstract

Maternal inflammation during pregnancy causes later-in-life alterations of the offspring’s brain structure and function. These abnormalities increase the risk of developing several psychiatric and neurological disorders, including schizophrenia, intellectual disability, bipolar disorder, autism spectrum disorder, microcephaly, and cerebral palsy. Here, we discuss how astrocytes might contribute to postnatal brain dysfunction following maternal inflammation, focusing on the signaling mediated by two families of plasma membrane channels: hemi-channels and pannexons. [Ca2+]i imbalance linked to the opening of astrocytic hemichannels and pannexons could disturb essential functions that sustain astrocytic survival and astrocyte-to-neuron support, including energy and redox homeostasis, uptake of K+ and glutamate, and the delivery of neurotrophic factors and energy-rich metabolites. Both phenomena could make neurons more susceptible to the harmful effect of prenatal inflammation and the experience of a second immune challenge during adulthood. On the other hand, maternal inflammation could cause excitotoxicity by producing the release of high amounts of gliotransmitters via astrocytic hemichannels/pannexons, eliciting further neuronal damage. Understanding how hemichannels and pannexons participate in maternal inflammation-induced brain abnormalities could be critical for developing pharmacological therapies against neurological disorders observed in the offspring.

Age-Dependent Activation of Pannexin1 Function Contributes to the Development of Epileptogenesis in Autosomal Dominant Sleep-related Hypermotor Epilepsy Model Rats

“…It has been demonstrated that pannexin1 and connexin43 form unopposed functional hemichannels in astrocytes [38][39][40][41][42]. Astroglial gliotransmitter release through connexin43-hemichannels was enhanced by decreasing the extracellular Ca 2+ level, whereas that through pannexin1-hemichannels was probably independent of the extracellular Ca 2+ level [23,27,28].…”

Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury

“…On the other hand, NO mediated S-nitrosylation of Px1 channels inhibits opening [ 140 ]. Therefore, these channels have been suggested to open via a different mechanism, as described in detail below [ 141 ].…”

Genetically engineered neural stem cells (NSCs) therapy for neurological diseases; state‐of‐the‐art

“…Finally, after injury, increased levels of inflammatory mediators and different cytokines avoid synaptic regeneration and exacerbate hypoxia and ischemia 6 . The formation of scars serves as a physical and chemical barrier, inhibiting synapses' extension and growth as well as nerve regeneration 7,8 . Indeed, numerous physiological processes, such as the availability of neurotrophic factors, axon regeneration, synaptic plasticity, and the microenvironment, contribute to the repair and regeneration of the central nervous system (CNS) following injuries, and the corresponding mechanisms are extremely complex 9 …”

“…6 The formation of scars serves as a physical and chemical barrier, inhibiting synapses' extension and growth as well as nerve regeneration. 7,8 Indeed, numerous physiological processes, such as the availability of neurotrophic factors, axon regeneration, synaptic plasticity, and the microenvironment, contribute to the repair and regeneration of the central nervous system (CNS) following injuries, and the corresponding mechanisms are extremely complex. 9 Throughout development, the brain and spinal cord are established from a small number of neural stem cells (NSCs) lining the neural tube.…”