Investigating how microcircuit abnormalities modulate brain-wide network dynamics to cause seizures across variant SCN1A mutations, using a zebrafish

本研究的目的是研究SCN1A功能缺失突变（编码电压门控钠通道）如何导致异常网络动力学导致癫痫发作，如在Dravet综合征患者中报道的那样。问题1 (Q1)：钠通道功能缺失突变如何导致神经元兴奋的矛盾增加？假设1：该突变优先导致抑制性神经元兴奋性降低，导致兴奋性神经元异常去抑制。问题2 (Q2)：不同的SCN1A突变如何导致患者不同的生物物理异常，从而导致共同的临床表型？假设2:SCN1A基因不同区域的突变不同程度地改变了钠通道的门控动力学，这些门控动力学向下游收敛，导致网络的超兴奋性。问题3 (Q3)：通过光片荧光显微镜（LSFM）和脑电图（EEG）测量，SCN1A突变如何导致异常的网络动力学？假设3:SCN1A突变导致LSFM和EEG中常见的神经元偶联异常。

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.