Investigating how microcircuit abnormalities modulate brain-wide network dynamics to cause seizures across variant SCN1A mutations, using a zebrafish
Lead Research Organisation:
King's College London
Department Name: Developmental Neurobiology
Abstract
The aim of this investigation is to examine how SCN1A loss-of-function mutations (encoding a voltage-gated sodium channel) lead to abnormal network dynamics resulting in epileptic seizures, as reported in patients with Dravet syndrome.
Question 1 (Q1): How does a loss-of-function sodium channel mutation lead to a paradoxical increase in neuronal excitation?
Hypothesis 1: The mutation preferentially leads to decreased excitability of inhibitory neurons causing aberrant disinhibition of excitatory neurons.
Question 2 (Q2): How do different SCN1A mutations, causing divergent biophysical abnormalities in patients, lead to a common clinical phenotype?
Hypothesis 2: Mutations along different regions of the SCN1A gene differentially alter sodium channel gating dynamics, which downstream converge to cause network hyper-excitability.
Question 3 (Q3): How do SCN1A mutations lead to abnormal network dynamics, as measured with light sheet fluorescence microscopy (LSFM) and electro-encephalogram (EEG)?
Hypothesis 3: SCN1A mutations result in common abnormalities in neuronal coupling across LSFM and EEG.
Question 1 (Q1): How does a loss-of-function sodium channel mutation lead to a paradoxical increase in neuronal excitation?
Hypothesis 1: The mutation preferentially leads to decreased excitability of inhibitory neurons causing aberrant disinhibition of excitatory neurons.
Question 2 (Q2): How do different SCN1A mutations, causing divergent biophysical abnormalities in patients, lead to a common clinical phenotype?
Hypothesis 2: Mutations along different regions of the SCN1A gene differentially alter sodium channel gating dynamics, which downstream converge to cause network hyper-excitability.
Question 3 (Q3): How do SCN1A mutations lead to abnormal network dynamics, as measured with light sheet fluorescence microscopy (LSFM) and electro-encephalogram (EEG)?
Hypothesis 3: SCN1A mutations result in common abnormalities in neuronal coupling across LSFM and EEG.
Publications
Burrows D
(2019)
The effects of antipsychotics on cingulate morphology and synaptic density in psychosis: A translational approach
in European Neuropsychopharmacology
Burrows DRW
(2020)
Imaging epilepsy in larval zebrafish.
in European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society
Liao M
(2019)
Targeted knockout of GABA-A receptor gamma 2 subunit provokes transient light-induced reflex seizures in zebrafish larvae.
in Disease models & mechanisms
Rosch R
(2019)
Functional Genomics of Epilepsy and Associated Neurodevelopmental Disorders Using Simple Animal Models: From Genes, Molecules to Brain Networks.
in Frontiers in cellular neuroscience
Title | Spiking network model |
Description | Built a spiking network model to analyse cascading dynamics in epilepsy. |
Type Of Material | Data analysis technique |
Year Produced | 2021 |
Provided To Others? | No |
Impact | None so far |
Description | Dev Neuro academy |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | We performed outreach for school students teaching them about neuroscience. |
Year(s) Of Engagement Activity | 2020 |