Characterization of synaptic alterations produced by mutation of the Dnm1 gene.
Abstract number :
3.122
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2017
Submission ID :
349964
Source :
www.aesnet.org
Presentation date :
12/4/2017 12:57:36 PM
Published date :
Nov 20, 2017, 11:02 AM
Authors :
Matthew McCabe, University of Vermont College of Medicine; Caitlynn Barrows, University of Vermont College of Medicine; Wayne N. Frankel, Columbia University Medical Center; and Matthew Weston, University of Vermont College of Medicine
Rationale: Dynamin-1 (Dnm1) is a large GTPase involved in vesicle endocytosis and synaptic vesicle recycling. De novo mutations in the DNM1 gene cause the epileptic encephalopathies (EE) Infantile Spasms and Lennox-Gastaut Syndrome in humans. Mice homozygous for a mutation in Dnm1 (Fitful), develop severe, lethal seizures, even when the mutation is selectively expressed in neurons, while heterozygous mice have a milder seizure phenotype. The Fitful mutation is a missense G-to-A substitution in exon 10a, which results in a change of alanine to threonine in the middle-domain of the Dnm1 protein. Given the synaptic function of the Dnm1 protein, and the fact that many EE-causing genes are predicted to affect synaptic transmission, it is likely that altered synaptic function underlies pathology arising from mutations in DNM1. Thus, understanding how synaptic function is altered by mutations in DNM1 is a critical first step toward understanding the mechanisms through which the mutation causes EE and, ultimately, developing targeted therapies. Methods: We cultured primary cortical neurons derived from homozygous and heterozygous Fitful and control mice and performed simultaneous whole-cell patch clamp recordings from glutamatergic and GABAergic neurons. We assessed a wide range of parameters including connection probability, synaptic strength, membrane excitability, and short-term plasticity of excitatory and inhibitory synaptic connections. Results: We found that homozygous Ftfl mutant neurons exhibit changes in fundamental properties of synaptic transmission, including altered short-term synaptic plasticity, while heterozygous mice have a milder phenotype. Conclusions: These findings suggest that altered short-term synaptic plasticity could be contributing to the pathology observed in DNM1-associated epileptic encephalopathies. Funding: N/A
Neurophysiology