The ionotropic
ATP-gated
P2X7 receptor is an important contributor to inflammatory signaling cascades via the release of Interleukin-1β, as well as having roles in cell death, neuronal plasticity and the release of
neurotransmitters. Accordingly, there is interest in targeting the
P2X7 receptor for the treatment of
epilepsy. However, the signaling pathways downstream of
P2X7 receptor activation remain incompletely understood. Notably, recent studies showed that
P2X7 receptor expression is controlled, in part, by
microRNAs (
miRNAs). Here, we explored
P2X7 receptor-dependent
microRNA expression by comparing
microRNA expression profiles of wild-type (wt) and
P2X7 receptor knockout mice before and after
status epilepticus. Genome-wide
microRNA profiling was performed using hippocampi from wt and
P2X7 receptor knockout mice following
status epilepticus induced by intra-amygdala
kainic acid. This revealed that the genetic deletion of the
P2X7 receptor results in distinct patterns of
microRNA expression. Specifically, we found that in vehicle-injected control mice, the lack of the
P2X7 receptor resulted in the up-regulation of 50
microRNAs and down-regulation of 35
microRNAs. Post-
status epilepticus,
P2X7 receptor deficiency led to the up-regulation of 44
microRNAs while 13
microRNAs were down-regulated. Moreover, there was only limited overlap among identified
P2X7 receptor-dependent
microRNAs between control conditions and post-
status epilepticus, suggesting that the
P2X7 receptor regulates the expression of different
microRNAs during normal physiology and pathology. Bioinformatic analysis revealed that genes targeted by
P2X7 receptor-dependent
microRNAs were particularly overrepresented in pathways involved in intracellular signaling,
inflammation, and cell death; processes that have been repeatedly associated with
P2X7 receptor activation. Moreover, whereas genes involved in signaling pathways and
inflammation were common among up- and down-regulated
P2X7 receptor-dependent
microRNAs during physiological and pathological conditions, genes associated with cell death seemed to be restricted to up-regulated
microRNAs during both physiological conditions and post-
status epilepticus. Taken together, our results demonstrate that the
P2X7 receptor impacts on the expression profile of
microRNAs in the brain, thereby possibly contributing to both the maintenance of normal cellular homeostasis and
pathological processes.