title: Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish.
abstract: Mutations in the synaptic machinery gene syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to childhood epilepsies and other neurodevelopmental disorders. Zebrafish STXBP1 homologs (stxbp1a and stxbp1b) have highly conserved sequence and are prominently expressed in the larval zebrafish brain. To understand the functions of stxbp1a and stxbp1b, we generated loss-of-function mutations using CRISPR/Cas9 gene editing and studied brain electrical activity, behavior, development, heart physiology, metabolism, and survival in larval zebrafish. Homozygous stxbp1a mutants exhibited a profound lack of movement, low electrical brain activity, low heart rate, decreased glucose and mitochondrial metabolism, and early fatality compared to controls. On the other hand, homozygous stxbp1b mutants had spontaneous electrographic seizures, and reduced locomotor activity response to a movement-inducing "dark-flash" visual stimulus, despite showing normal metabolism, heart rate, survival, and baseline locomotor activity. Our findings in these newly generated mutant lines of zebrafish suggest that zebrafish recapitulate clinical phenotypes associated with human syntaxin-binding protein 1 mutations.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Grone
authors.affiliation: Molecular Medicine & Clinical Neurophysiology Laboratories, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Marchese
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Kyla R
authors.initials: KR
authors.lastname: Hamling
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Maneesh G
authors.initials: MG
authors.lastname: Kumar
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.|Department of Biology, Colby College, Waterville, Maine, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Krasniak
authors.affiliation: Molecular Medicine & Clinical Neurophysiology Laboratories, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Sicca
authors.affiliation: Molecular Medicine & Clinical Neurophysiology Laboratories, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Manisha
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Baraban
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051938:Munc18 Proteins; D029961:Zebrafish Proteins