Biology subjects

Espina, J. E. C.

Publications and source records attributed to Espina, J. E. C..

3 recordsLinked to original sources

bioRxiv2026

JAK inhibition overcomes first-line drug resistance in a pre-clinical model of epilepsy

One-third of people with epilepsy continue to have seizures despite antiseizure medications (ASMs), and available therapies often fail to improve disabling cognitive comorbidities. Patients with drug resistant epilepsy report that the adverse effects of medications along with their comorbidities can have a greater negative impact on the quality of life than seizures. We previously identified recurrent JAK/STAT3 activation in chronic epilepsy and showed that transient treatment with the JAK inhibitor tofacitinib (CP690550) durably suppresses seizures and restores cognition in mice. Here, we tested CP690550 as an add-on therapy after failure of carbamazepine (CBZ), a common first line treatment for epilepsy, in a mouse model of multifocal temporal lobe epilepsy. In CBZ-resistant animals, dual therapy with CP690550 reduced median seizure frequency and time spent seizing by an order of magnitude; most dual therapy responders had no observed behavioral seizures during treatment. CP690550 also restored spatial working and short-term memory. We found that cognitive rescue was independent of seizure response. Our work suggests that JAK/STAT inhibition can overcome ASM nonresponse while independently improving epilepsy-associated cognitive dysfunction.

neuroscience↗

bioRxiv2026

H3K27me3 maintains baseline network excitability after status epilepticus

The processes by which epileptic insults precipitate the molecular, cellular, and network alterations in the brain that lead to epilepsy are poorly understood. We previously discovered that after status epilepticus (SE - an epilepsy inducing severe bout of seizures) the H3K27 methylase Enhancer of Zeste Homolog 2 (EZH2) is robustly induced and drives repression of genes. Both systemic pharmacological inhibition of EZH2 and deletion of EZH2 in neurons exacerbates epilepsy progression, suggesting that acute EZH2 induction may exert a net protective effect against disease progression chronically. However, the mechanisms underlying EZH2-mediated control of the putative protective and pathological pathways in disease progression are still unknown. To interrogate the mechanisms of EZH2 function post-SE, we used bulk CUT&RUN- sequencing against H3K27me3 in tandem with bulk RNA-sequencing in hippocampi of naive and 4d. post-SE mice to profile epigenomic and transcriptomic changes. Differential peak analysis showed that H3K27me3 was enriched both at loci pre-marked by H3K27me3 in the naive hippocampus as well as in loci that were de novo methylated after SE, consistent with the SE-dependent induction of EZH2 protein levels. Multi-omic integration of CUT&RUN and RNA-seq data revealed a module of genes that were coordinately H3K27me3 enriched, transcriptionally repressed, and annotated to ontological terms involved in neuronal signaling and network excitability. This result suggests that EZH2 induction may function in part to control network excitability after injury. To test this, we treated mice acutely post-SE with the EZH2 inhibitor UNC1999 and found that EZH2 inhibition attenuated H3K27me3 induction and dampened repression of target network excitability genes in response to SE. Functionally, UNC1999 treatment significantly increased seizure probability acutely and exacerbated disease severity in the chronic period. Taken together, these results suggest that EZH2 induction after injury may function to maintain network excitability to lower seizure probability acutely to protect against disease progression.

neuroscience↗

bioRxiv2025

Motion sequencing reveals hidden patterns of repetitive behavior in a mouse model of epilepsy

Epilepsy is the 4th most prevalent neurological condition with 50 million cases worldwide. Patients with epilepsy bare a disproportionate burden of cognitive decline and psychiatric disorders which remain poorly understood and go unaddressed by current anti-epileptic treatments. Furthermore, pre-clinical work on behavioral comorbidities can be hampered by current testing frameworks which rely on well-defined, discreet tests with limited repeatability. Recent work has demonstrated a role for machine learning modalities such as Motion Sequencing (MoSeq) in assessing behavioral differences between naive and epileptic. In this study we combined MoSeq with a novel analysis pipeline to uncover repetitive behaviors in chronically epileptic mice. These repetitive behaviors emerge alongside epilepsy specific racing behaviors which persist in epileptic mice as disease progresses. We show that epileptic mice have more fragile and dispersed behavioral networks. Finally, we test this pipeline using the FDA approved anti-seizure medication carbamazepine, showing a rescue of racing syllable and a partial rescue of behavioral network dispersion. Together, these results lay a groundwork for extracting clinically relevant phenotypes from MoSeq data throughout disease progression.

neuroscience↗