Roles of glycinergic neurons in Dravet syndrome-associated disordered breathing and mortality

摘要 德拉韦综合征(DS)是一种严重的癫痫类型，SUPEP的发生率很高。呼吸性 失败是SUDEP的主要原因，DS患者经常表现出呼吸紊乱。 然而，DS的呼吸功能障碍的潜在机制尚不清楚。证据 提示皮层癫痫激活抑制投射以抑制脑干功能和 导致死亡；然而，一种尚未探索的可能性是DS相关突变直接 影响脑干呼吸中枢，是癫痫和癫痫的共同底物 呼吸功能障碍。我们最近发现Scn1a转录本在 脑干抑制神经元及DS相关Scn1a突变(A1783V)的表达 抑制性神经元导致细胞自主丧失神经活动并扰乱 在细胞和整个动物水平上的呼吸功能。因此，我假设损失了 SCN1A的功能直接影响脑干呼吸控制。为了测试这一点，我将扰乱Scn1a 全局功能(Scn1a-/+)，特别是在所有VGAT+抑制神经元中，仅在甘氨酸能神经元中 神经元(GlyT2：A1783V)，并确定这些动物是否表现出呼吸紊乱， 癫痫发作或过早死亡(目标1)，以及呼吸神经元细胞活动改变(目标2)。 这项工作将为了解甘氨酸能神经元在DS中的作用提供新的见解，并确定 Scn1a功能丧失直接影响脑干功能的程度。

Summary Dravet syndrome (DS) is a severe form of epilepsy with a high rate of SUPEP. Respiratory failure is a leading cause of SUDEP, and DS patients' frequently exhibit disordered breathing. However, mechanisms underlying respiratory dysfunction in DS are unknown. Evidence suggests cortical seizures activate inhibitory projections to suppress brainstem function and result in death; however, a yet unexplored possibility is that DS-associated mutations directly affect brainstem respiratory centers and serve as a common substrate for both seizure and respiratory dysfunction. We recently showed that Scn1a transcript is highly expressed in brainstem inhibitory neurons, and expression of a DS-associated Scn1a mutation (A1783V) in inhibitory neurons resulted in cell autonomous loss of neural activity and disruption of respiratory function at the cellular and whole-animal levels. Therefore, I hypothesize that loss of Scn1a function directly impacts brainstem respiratory control. To test this, I will disrupt Scn1a function globally (Scn1a-/+), specifically in all VGAT+ inhibitory neurons and only in glycinergic neurons (GlyT2:A1783V) and determine whether these animals exhibit disordered breathing, seizures or premature death (Aim 1), and altered cellular activity of respiratory neurons (Aim 2). This work will provide novel insight into roles of glycinergic neurons in DS, and determine the extent to which loss of Scn1a function directly affect brainstem function.