Murine Knockout Model of 4-Hydroxybutyric Aciduria

人类琥珀酸半醛脱氢酶缺乏症[甘露-羟丁酸(GHB)酸]是 两种影响GABA神经递质系统的神经遗传疾病，其中一种是两种神经活性化合物， Gab A和GHb累积。SSADH“”小鼠表现出早期失神发作，并演变为致死性全身发作 惊厥性癫痫，类似于临床综合征中观察到的癫痫表型。我们的主要目标是描绘 SSADH缺乏症多变临床表现的基本机制。在当前的项目中，我们将 解决以下假设(H)和AIMS(A)：HI：广泛针对GABA能/GH能的药物治疗 SSADH小鼠的受体系统将延长寿命，并为人类提供治疗范例的洞察力。阿尔：到 在SSADH“”小鼠身上检测新的药疗方法，以挽救这些动物的早期死亡并探索 存活的成年突变体的神经病理学。H2。SSADH“‘小鼠失神发作是由GHb升高引起的，而 全身性惊厥发作和癫痫持续状态是由GABAAR介导的抑制减少引起的 GABA依赖的GABA受体下调。A2.1)评估羟基丁酸在失神发作中的作用及其作用 失神发作在SSADH‘’小鼠全身性惊厥发作发展中的作用 旨在抑制运动性癫痫发作和癫痫持续状态的药物疗法；a2.2)定义 小鼠运动性惊厥和失神惊厥中的GABAA受体(GABAAR)及其与癫痫的关系 全身性惊厥发作；A2.3)确定GABAAR受体电导和调节功能 GABR受体在小鼠运动性惊厥和失神惊厥中的作用；以及2.4)以确定 过量的GABA和/或GHB对GABA功能和亚基组成的影响。H3.系统性的温室气体清除主要是 受肝脏中存在的SSADH活性总量的限制。目标3：使用SSADH进行肝脏再灌流。 利用选择性生长优势，对SSADH**小鼠的肝细胞数进行了估算。 纠正伽玛-羟丁酸尿症所必需的肝细胞。实现我们目标的方法包括 治疗学、神经生理学和神经化学、肝细胞再生等。SSADH型“‘”鼠标 模型为理解人类SSADH相关的病理生理学提供了有力的研究工具 缺乏症。我们的实验方法对人类患者具有治疗意义，并可能对 了解癫痫发生的基本机制，远远超出SSADH缺乏的范围。

Human succinic semialdehyde dehydrogenase (SSADH) deficiency [ganmia-hydroxybutyric (GHB) aciduriaj is one of the tew neurogenetic disorders affecting the GABA neurotransmitter system, and one in which two neuroactive compounds, GAB A and GHB, accumulate. SSADH'''mice manifest early absence seizures which evolve into lethal generalized convulsive epilepsy, similar to seizure phenotypes observed in the clinical syndrome. Our main objectiveis to delineate basic mechanisms at play in the protean clinical manifestationsin SSADH deficiency. In the current project, we will address the following hypotheses (H) and aims (A): HI: pharmacotherapy broadly targeting the GABAergic/GHBergic receptor systems in SSADH"" mice will extend lifespan and provide insight into treatment paradigms for humans. Al: To examine novel phurmacotherapeutics in SSADH"''mice in order to rescue these animals from early lethality and explore neuropathology in surviving, adult mutants. H2. Absence seizures in SSADH"' mice result from elevated GHB, whereas generalized convulsive seizures and status epilepticus arise from decreased GABAAR-mediatedinhibition induced by GABA-dependent down regulation of GABA^ receptors. A2.1) to assess the role of GHB in absence seizures and the role of absence seizures in the development of generalized convulsive seizures in SSADH''' mice, and to examine pharmacotherapeutics aimed at suppressing motor seizures and status epilepticus; A2.2) to define perturbations of the GABAA receptor (GABAAR) in SSADH"' mice ¿ motor seizures and ¿ absence seizures and the relation of these to the onset of generalized convulsive seizures; A2.3) to ascertain GABAAR receptor conductances and the regulatory functions of GABABR receptors in SSADH"' mice ¿ motor seizures and ¿ absence seizures; and 2.4) to determine the effect of excess GABA and/or GHB on GABAAR function and subunit composition. H3. Systemic GHB clearance is primarily limited by the total amount of SSADH activitypresent in liver. Aim 3: To perform liver repopulation with SSADH'" hepatocytes in SSADH** mice utilizing a selective growth advantage, in order to estimate the number of SSADH^ hepatocytes necessary to correct gamma-hydroxybutyric aciduria. The methods to achieve our objectives include therapeutics, neurophysiology and neurochemistry, and hepatocyte repopulation, among others. The SSADH"'" mouse model represents a powerful investigativetool for understanding thepathophysiology associated with human SSADH deficiency. Our experimental approach possesses therapeutic import for human patients, and may have ramifications for understanding the fundamental mechanisms of epileptogenesis that extend far beyond SSADH deficiency.