Epileptic encephalopathy (STXBP1/Munc18-1)

Mutations in STXBP1 cause encephalopathy, also diagnosed as Ohtahara Syndrome, Dravet syndrome and atypical Rett syndrome.

In humans, de novo mutations in the STXBP1 gene (alias Munc18-1) lead to early infantile epileptic encephalopathies that are characterized by infantile epilepsy, intellectual disability, and can include autistic features. The protein encoded by this gene plays a critical role in synaptic neurotransmitter release. Patients receive a diverse range of primary diagnosis, including Ohtahara Syndrome, Dravet syndrome and atypical Rett syndrome. More information for patients and clinicians about this rare genetic disorder can be found on website of the STXBP1 Center Amsterdam.

Stxbp1 mouse model

The symptoms observed in STXBP1 patients are mimicked in Stxbp1+/- mice with a heterozygous loss of this important gene. The reduction in STXBP1 protein leads to changes in cognitive function and general behaviour as well as epileptic-like activity as detected with Electroencephalography (EEG). Over the past decade, the team at Sylics has collaborated with the researchers at the STXBP1 Center in Amsterdam to characterise this mouse model in detail (Kovacevic 2018, Brain).

This figure summarizes the diverse primary diagnoses that patients with STXBP1 mutations received, courtesy of STXBP1 Center Amsterdam.

Epileptic-like discharges in the Stxbp1 model

In freely moving Stxbp1+/- mice with telemetric EEG implants, an increased number of epileptic-like spike wave discharges (SWD) can be detected. These SWDs in the EEG occasionally coincide with behavioral twitches and jumps that can be noticed on video footage as well as with an EMG electrode in the neck muscle.  These could partially be suppressed by an anti epileptic drug (AED levetiracetam). c-Fos immunohistochemistry showed an increased number of recently active neurons, likely related to this epileptic-like activity (Kovacevic 2018, Brain).

Cognitive impairment in the Stxbp1 mouse model

The epileptic-like activity in the brain of Stxbp1 mutant mice does not preclude cognitive testing. In line with observations in STXBP1 patients, cognitive deficits can be detected. Subtle learning and memory deficits in Stxbp1+/- mice are detectable in the reversal learning protocol of the Barnes Maze (Kovacevic 2018, Brain). Furthermore, reproducible deficits in a freezing response were detected in different Stxbp1+/- mutant lines in a fear conditioning test.

Anxiety and general behavioral changes in the Stxbp1 model

When observed in an automated home-cage (PhenoTyper) without the stress of being handled by humans, Stxbp1+/- mice show differences in comparison with WT litter mates. These differences are observed in a wide range of behaviors that can be measured using the analysis of spontaneous behavior in these cages. Furthermore, different Stxbp1 models have been shown to show increased anxiety (Hager et al. 2014), which at Sylics is assessed at the Elevated Plus Maze.

Kovacevic et al (2018) Brain

Kovacevic J, Maroteaux G, Schut D, Loos M, Dubey M, Pitsch J, Remmelink E, Koopmans B, Crowley J, Cornelisse LN, Sullivan PF, Schoch S, Toonen RF, Stiedl O, Verhage M. Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy. Brain. 2018 May 1;141(5):1350-1374. doi: 10.1093/brain/awy046. PMID: 29538625; PMCID: PMC5917748. https://pubmed.ncbi.nlm.nih.gov/29538625/

Keywords: STXBP1, Munc-18, EEG

Hager et al. (2014) Behav Brain Res

Munc18-1 haploinsufficiency results in enhanced anxiety-like behavior as determined by heart rate responses in mice. Hager T, Maroteaux G, Pont Pd, Julsing J, van Vliet R, Stiedl O. Behav Brain Res. 2014 Mar 1;260:44-52. doi: 10.1016/j.bbr.2013.11.033. Epub 2013 Dec 1. PMID: 24304718. https://pubmed.ncbi.nlm.nih.gov/24304718/

Keywords: STXBP1, Munc18

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