Characterization of the Expression of the ATP-Gated P2X7 Receptor Following Status Epilepticus and during Epilepsy Using a P2X7-EGFP Reporter Mouse

Abstract

Mounting evidence suggests that the ATP-gated P2X7 receptor contributes to increased hyperexcitability in the brain. While increased expression of P2X7 in the hippocampus and cortex following status epilepticus and during epilepsy has been repeatedly demonstrated, the cell type-specific expression of P2X7 and its expression in extra-hippocampal brain structures remains incompletely explored. In this study, P2X7 expression was visualized by using a transgenic mouse model overexpressing P2X7 fused to the fluorescent protein EGFP. The results showed increased P2X7-EGFP expression after status epilepticus induced by intra-amygdala kainic acid and during epilepsy in different brain regions including the hippocampus, cortex, striatum, thalamus and cerebellum, and this was most evident in microglia and oligodendrocytes. Colocalization of P2X7-EGFP with cell type-specific markers was not detected in neurons or astrocytes. These data suggest that P2X7 activation is a common pathological hallmark across different brain structures, possibly contributing to brain inflammation and neurodegeneration following acute seizures and during epilepsy.

Astrocytic and Oligodendrocytic P2X7 Receptors Determine Neuronal Functions in the CNS

“…These findings were confirmed by microglia- and oligodendrocyte-specific P2X7 deletion and a novel P2X7-specific nanobody. By using this model mouse, status epilepticus induced by intra-amygdala injection of kainic acid confirmed co-localization of P2X7-EGFP with cell-type-specific markers in oligodendrocytes, but not in neurons or astrocytes (Morgan et al, 2020 ).…”

Astrocytes respond to a neurotoxic Aβ fragment with state-dependent Ca2+ alteration and multiphasic transmitter release

“…One possible mechanism underlying P2Y1 activation by Aβ might be that it activated ATP-releasing pathways in astrocytes. In spinal cord and hippocampal astrocytes, ATP release was suggested to be mediated by the pore-forming P2X7 receptor [ 95 ], although its expression in astrocytes of specific regions was called into reconsideration [ 59 ]. We observed that P2X7 antagonist A740003 (20 µM) [ 35 ] failed to affect Aβ-triggered Ca 2+ signal, echoing the absence of an effect of the wide-spectrum P2X blocker TNP-ATP (Fig.…”

Antagonistic Roles of P2X7 and P2Y2 Receptors in Neurodegenerative Diseases

“…Similarly to AD, P2X7R protein levels are upregulated in regions damaged by seizures and in the hippocampus of animal models. As previously summarized (Engel et al, 2012;Engel et al, 2016), the lack of the P2X7R promotes susceptibility to status epilepticus, while P2X7R antagonists are potent anticonvulsants (Engel et al, 2012;Engel et al, 2016;Beamer et al, 2017;Zeng et al, 2017;Burnstock and Knight, 2018;Song et al, 2019;Doǧan et al, 2020;Hong et al, 2020;Morgan et al, 2020). P2Y2R knockout animals present higher glutamate release in the hippocampus (Alhowail et al, 2020), and uridine triphosphate administration had sleep-promoting and anti-epileptic actions, improved memory function and affected neuronal plasticity (Dobolyi et al, 2011;Alves et al, 2017).…”