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Introduction: Although there are numerous treatment options already available for epilepsy, over 30% of patients remain resistant to these antiseizure medications (ASMs). Historically, ASM discovery has relied on the demonstration of efficacy through the use of 'traditional' acute invivo seizure models (e.g. maximal electroshock, subcutaneous pentylenetetrazol, and kindling). However, advances in genetic sequencing technologies and remaining medical needs for people with treatment-resistant epilepsy or special patient populations have encouraged recent efforts to identify novel compounds in syndrome-specific models of epilepsy. Syndrome-specific models, including Scn1a variant models of Dravet syndrome and APP/PS1 mice associated with familial early-onset Alzheimer's disease, have already led to the discovery of two mechanistically novel treatments for developmental and epileptic encephalopathies (DEEs), namely cannabidiol and soticlestat, respectively. Areas covered: In this review, the authors discuss how it is likely that next-generation drug discovery efforts for epilepsy will more comprehensively integrate syndrome-specific epilepsy models into early drug discovery providing the reader with their expert perspectives. Expert opinion: The percentage of patients with pharmacoresistant epilepsy has remained unchanged despite over 30 marketed ASMs. Consequently, there is a high unmet need to reinvent and revise discovery strategies to more effectively address the remaining needs of patients with specific epilepsy syndromes, including drug-resistant epilepsy and DEEs. [ABSTRACT FROM AUTHOR]

Proper transport of RNAs to synapses is essential for localized translation of proteins in response to synaptic signals and synaptic plasticity. Alzheimer's disease (AD) is a neurodegenerative disease characterized by accumulation of amyloid aggregates and hyperphosphorylated tau neurofibrillary tangles followed by widespread synapse loss. To understand whether RNA synaptic localization is impacted in AD, we performed RNA sequencing on synaptosomes and brain homogenates from AD patients and cognitively healthy controls. This resulted in the discovery of hundreds of mislocalized mRNAs in AD among frontal and temporal brain regions. Similar observations were found in an APPswe/PSEN1dE9 mouse model. Furthermore, major differences were observed among circular RNAs (circRNAs) localized to synapses in AD including two overlapping isoforms of circGSK3β, one upregulated, and one downregulated. Expression of these distinct isoforms affected tau phosphorylation in neuronal cells substantiating the importance of circRNAs in the brain and pointing to a new class of therapeutic targets. Author summary: Synaptic plasticity is the foundation for cognition and describes the process by which synaptic connections between neurons are formed, strengthened, or weakened based on signals transmitted by neighboring neurons. Essential to this process is the ability of synapses to respond rapidly to signals and restructure their morphology by translating proteins from a pool of localized mRNAs which is orchestrated by a complex cytoskeletal trafficking system. Given that synapse loss is a cardinal feature of Alzheimer's disease (AD), we RNA sequenced fractionated synaptic particles from brain samples from AD patients and healthy controls to determine whether RNA localization to synapses is impacted in AD. We discovered hundreds of mislocalized mRNAs as well as circular RNAs (circRNAs) which are non-coding isoforms shown to play critical regulatory roles in the brain. Among our data, we discovered two isoforms of circGSK3β, one upregulated, and one downregulated in AD. Expression of these isoforms in neuronal culture was shown to affect tau phosphorylation, dysregulation of which is a hallmark of AD. These findings point to RNA localization and circRNAs as key components to understanding AD pathology and implicate new targets for AD therapies. [ABSTRACT FROM AUTHOR]

Background: Presenilin 2 (PSEN2) is one of three deterministic risk genes that increases the risk of early‐onset Alzheimer's Disease. People with PSEN2 variants have increased risk of unprovoked seizures versus age‐matched unaffected individuals yet few studies have interrogated the contributions of PSEN2 on seizure susceptibility. Critically, PSEN proteolytic capacity may be a novel regulator of hippocampal kainate‐type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring agonist for KARs that evokes sustained, severe seizures and status epilepticus (SE). We thus hypothesized PSEN2‐KO mice would demonstrate reduced KA‐SE latency, increased SE severity, worsened outcomes 7‐days later, and have altered hippocampal KAR expression versus similarly treated WT mice. Method: Using a repeated low‐dose systemic KA administration model to evoke SE, we quantified the latency to SE and extent of SE‐induced neuropathology in 3–4‐month‐old male and female PSEN2‐KO versus WT mice (n = 10‐16 mice/group/sex). GluK5, a KAR subunit, expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA‐SE or sham to define the impacts of PSEN2 deletion and SE on hippocampal KAR expression. Result: Regardless of sex, PSEN2‐KO mice were more susceptible to KA‐SE than WT mice. Male PSEN2‐KO mice progressed to SE faster than WTs (78.6±25.3 versus 98.2±16.0 min; t = 2.43, p = 0.027); female PSEN2‐KO mice were also more susceptible to KA‐SE relative to WTs (85.3±32.2 versus 112.2±15.4 min; t = 2.45, p = 0.022). Basal GluK5 expression did not differ between sexes or genotypes. However, in male mice 7‐days post‐KA‐SE insult GluK5 expression was significantly increased over basal levels in WT mice (p = 0.0028), but PSEN2‐KO mice GluK5 levels were unchanged from basal expression (p = 0.9819). Regardless of genotype, female mice GluK5 levels were unchanged from basal expression at 7‐days post‐KA‐SE insult, revealing sex differences in post‐SE outcomes. Conclusion: Loss of normal PSEN2 function increases susceptibility to KA‐induced seizures and SE, which cannot be explained by basal GluK5 expression differences. However, increased GluK5 expression in male WT relative to PSEN2‐KO mice 7‐days post KA‐SE, further substantiates a role of PSEN2 in KAR availability. Sex differences in GluK5 and GFAP were also apparent post‐SE. [ABSTRACT FROM AUTHOR]