Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/395566

Opposing effects of prostaglandin receptor EP2 signaling in mouse immune cells and neurons after status epilepticus

Varvel, N. H.·Chen, D.·Biegel, A.·Dingledine, R.
View original source ↗Export metadata ↓

Abstract

A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2 mediated activation of prostaglandin EP2 receptors. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and forebrain neurons. Removal of myeloid cell EP2 dampened induction of hippocampal IL-6, prevented erosion of the blood-brain barrier, accelerated weight regain, and relieved ptosis following SE. Elimination of EP2 receptor from neurons enhanced neuronal injury, elevated hippocampal induction of the pro-inflammatory cytokines, TNF and Ccl2, promoted deterioration of the blood-brain barrier, delayed weight recovery, and worsened animal posture and activity. Taken together these data highlight the complexities in neuroinflammatory signaling, wherein activation of EP2 receptors in innate immune cells is deleterious but neuronal EP2 signaling is protective. Effective treatments targeting brain prostaglandin signaling pathways should be cell targeted to be optimally effective.\n\nSignificance StatementSeizures reduce quality of life, promote the development of epilepsy, and can be fatal. We previously identified inflammation, via prostaglandin receptor EP2 activation, as a driver of undesirable seizure-induced effects. However, the relevant EP2-expressing cell types remain unclear. We identify innate immune cells as a driver of the EP2-related negative consequences of seizures, whereas neuronal EP2 signaling is protective. Genetic removal of EP2 from immune cells was beneficial, accelerating weight gain and limiting behavioral deficits. Elimination of EP2 from neurons was harmful, worsening behavioral deficits and promoting neuronal damage. These findings enhance our understanding of the complex inflammatory processes engaged after seizures and will assist in the development of beneficial therapies to enhance quality of life in individuals susceptible to seizures.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Varvel, N. H., Chen, D., Biegel, A., Dingledine, R.. 2018-08-19. Opposing effects of prostaglandin receptor EP2 signaling in mouse immune cells and neurons after status epilepticus. https://doi.org/10.1101/395566

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Why probe registration is crucial for infant fNIRS and HD-DOT? An evaluation across 49 newborns

Source-detector probe registration, i.e., the mapping of optode positions on the scalp to their true anatomical locations in head/brain space, is crucial for brain imaging with fNIRS or HD-DOT. While individual, MRI-based registration is desirable, it is not always feasible, motivating the development of alternative registration approaches. This study uses the STORM-Net registration protocol and quantifies the variation of cap alignment in a cohort of 49 newborns to evaluate how this affects reconstructed images using HD-DOT. Relative to a centrally aligned template, the cohort showed a median probe-position error of 10.12 mm, while the least and most misaligned subjects exhibited mean errors of 4.41 mm and 20.60 mm, respectively. The results demonstrate that the level of cap misalignment typically observed in newborn imaging can affect the spatial accuracy of reconstructed functional images, particularly in cases with larger probe displacements. These findings provide a quantitative basis for adopting more conservative interpretations of group-level functional brain activity and functional connectivity results, and strongly support the routine use of registration methods in infant HD-DOT studies.

neuroscience↗
bioRxiv2026

Multimodal characterization of putative pan-inhibitory viral constructs in macaque monkeys

Transgenic approaches and validated viral vector toolboxes have advanced our understanding of how inhibitory neurons shape cognition and motor control in mice and other rodents. However, such advances have been elusive in non-human primates (NHPs). While many studies demonstrate expression of reporter proteins, few studies have provided clear quantitative evidence of whether these viral constructs can be reliably used for assessment of in vivo and in vitro function in primates, which, in turn, has hindered widespread adoption by NHP researchers. Here, we characterize putative pan-inhibitory cell targeting vectors engineered with regions from the Dlx5-6 intergenic domain. Pan-inhibitory viral vectors are attractive because they enable ground-truth optotagging and modulation of multiple inhibitory subtypes in the same animal and, when combined with machine learning approaches, enable cell-type classifiers for NHPs. We combined in vivo anesthetized electrophysiological recordings, in vitro slice electrophysiology, and immunohistochemistry across seven rhesus macaque monkeys to assess the specificity, completeness and efficacy of three constructs in multiple sensory and higher-order association cortices. The vectors reliably restricted transgene expression to inhibitory neurons (81-97%). However, of the local GABAergic neurons only 32-64% expressed the transgene, depending on the construct. This incompleteness arose in part from uneven coverage across subtypes, with strong transgene expression in parvalbumin-positive interneurons (~60-90%), sparse expression in calbindin-positive interneurons (~1-7%), and near-complete avoidance of calretinin-positive interneurons. A construct pairing DLX2.0 with ChrimsonR was excellent for in vivo optotagging, while h56D paired with bReaChES most effectively suppressed neural activity in vivo. In the slice, activating terminals of transgene-expressing neurons optically evoked inhibitory currents in coupled pyramidal neurons confirming transsynaptic functionality of these constructs and their use for inhibitory circuit-specific synaptic assessments and manipulation. Collectively, the results provide rigorous functional characterization, and quantitative guidance for NHP researchers seeking to deploy GABAergic cell-type-specific tools in their experiments.

neuroscience↗
bioRxiv2026

Glider compositionality and information capacity in an E/I-balanced neuronal automaton

In cellular automata, localized activity patterns called gliders propagate and interact to carry and transform information. Whether neuronal networks can harness this computational power remains unclear. Here, we demonstrate that a cortical network model with separate excitatory and inhibitory populations, graded cellular activity and uniform local connectivity spontaneously generates diverse, interacting gliders. An analytical reduction identifies the cellular conditions sustaining propagation of the dominant G-glider. Distinct gliders can assemble into growing structures that emit other glider types. Near excitation/inhibition balance, sparse glider dynamics coexist with high computational capacity, measured by input differentiation and generalization, with local capacity varying across space and time. Strong mutual inhibition between interneurons instead permits metastatic proliferation with low computational capacity. These findings connect cellular automata to neuronal information processing and identify interacting gliders as a candidate mechanism for dynamic plasticity: the reorganization of computation within an unchanged synaptic architecture.

neuroscience↗