Previously, we have briefly introduced you to the Stxbp1 +/- mouse model of early infantile epileptic encephalopathies. Patients with a mutation in the STXBP1 gene (Syntaxin-binding protein 1, encoding the presynaptic protein Munc18-1) can receive a variety of different diagnoses (i.e., epileptic encephalopathy, Dravet syndrome, Ohtahara syndrome, West syndrome), but they all present with epilepsy, intellectual disability and/or autistic traits (Stamberger et al. 2016). Although STXBP1-related disorders are rare, STXBP1 is the 5th most common cause of genetic forms of epilepsy (Symonds et al. 2020). The symptoms observed in STXBP1 patients are mimicked in Stxbp1+/- mice with a heterozygous loss of this important gene, proving to be a valid preclinical research mouse model for STXBP1 haploinsufficiency.
Spike-wave discharges (SWDs) are a form of epileptic-like activity that can be accompanied by motor effects of epileptic-like neural activity. Similar to patients, both SWDs and motor effects are frequently detected by us via wireless EEG, video and accelerometer recordings in freely moving Stxbp1 +/- mice. Therefore, both novel anti-epileptic drugs (AEDs) as well as gene-targeting compounds can be evaluated in the Stxbp1 +/- mouse model.
FIGURE 1. Spike-wave discharge observed on EEG recordings of Stxbp1 +/- mouse at rest.
Current research suggests that changes in presynaptic proteins that regulate synaptic transmission lead to epileptic phenotypes, which in turn can be alleviated by compounds that act presynaptically (Kovačević et al. 2018). Commonly prescribed AEDs such as Levetiracetam and Lamotrigine have a presynaptic mode of action, and therefore represent readily available candidates to test inhibition of EEG abnormalities in our mouse model for disorders caused by mutations in the presynaptic Stxbp1 gene.
In line, we observe that in the Stxbp1 mouse model, SWDs are suppressed with Levetiracetam (published together with Kovačević et al., 2018 as well as internal data below) and Lamotrigine (internal data below); consistent with their clinical applications in STXBP1 patients. This finding further confirms the suitability and translational relevance of our STXBP1 model in preclinical efficacy testing of novel AEDs.
FIGURE 2. The epilepsy-like phenotype in Stxbp1 +/- mice is suppressed with standard of care AEDs Levetiracetam and Lamotrigine. Average frequency of detected SWDs during 6 hours of video recording following administration of saline, Levetiracetam (50 mg/kg, i.p,) and Lamotrigine (50 mg/kg, i.p.) (**P<0.01 saline vs Levetiracetam; ***P<0.001 saline vs Lamotrigine).
In the figure below, we show that the stable epileptic-like phenotype of Stxbp1 +/- mice allows us to perform longitudinal collection of EEG data over several weeks. Such study design allows us to measure pre-treatment SWD activity, followed by EEG measurements after several weeks following compound dosing or AAV injections. Combined with our on-site breeding capacities, biotechnical expertise, and flexible start times, efficacy testing of gene-targeting interventions can start as early as post-natal day 1.
FIGURE 3. Stxbp1 +/- mice aged from 16 weeks to 20 weeks show stable epileptic-like phenotype. Average frequency of SWDs per hour in the Stxbp1 +/- mice assessed over a period of several weeks (mean ± SEM).
In addition, we consistently detect cognitive deficits in the Stxbp1 +/- mouse model, which are typically observed in patients with STXBP1 mutations. We have functionally characterized the Stxbp1 +/- mouse model and detect reproducible behavioural phenotypes across multiple behavioural readouts (for e.g. Fear Conditioning, Automated home-cage analysis, Barnes maze).
FIGURE 4. c-Fos expression in Stxbp1 +/- mice. Representative IHC images of c-Fos+ neurons in prefrontal cortex, primary motor cortex, and somatosensory cortex in BL6 Stxbp1 +/− mice. Published by Kovačević et al. 2018.
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