Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark; Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
Neuroscience. 2022 Sep 1;499:142-151. doi: 10.1016/j.neuroscience.2022.07.020. Epub 2022 Jul 22.
Synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein that binds levetiracetam and is involved in neurotransmission via an unknown mechanism. SV2A-immunoreactivity is reduced in animal models of epilepsy, and in postmortem hippocampi from patients with temporal lobe epilepsy. It is not known if other regions outside the hippocampus are affected in epilepsy, and whether SV2A expression is permanently reduced or regulated over time. In this study, we induced a generalized status epilepticus (SE) by systemic administration of lithium-pilocarpine to adult female rats. The brains from all animals experiencing SE were collected at different time points after the treatment. The radiotracer, [C]-UCB-J, binds to SV2A with high affinity, and has been used for in vivo imaging as an a-proxy marker for synaptic density. Here we determined the level of tritiated UCB-J binding by semiquantitative autoradiography in the cerebral cortex, hippocampus, thalamus, and hypothalamus, and in cortical subregions. A prominent and highly significant reduction in SV2A binding capacity was observed over the first days after SE in the cerebral cortex and the hippocampus, but not in the thalamus and hypothalamus. The magnitude in reduction was larger and occurred earlier in the hippocampus and the piriform cortex, than in other cortical subregions. Interestingly, in all areas examined, the binding capacity returned to control levels 12 weeks after the SE comparable to the chronic epileptic phase. These data indicate that lithium-pilocarpine-induced epileptogenesis involves both loss and gain of synapses in the in a time-dependent manner.
突触小泡糖蛋白 2A（SV2A）是一种跨膜蛋白，与左乙拉西坦结合，并通过未知机制参与神经传递。癫痫动物模型和颞叶癫痫患者死后海马区 SV2A 免疫反应性降低。目前尚不清楚癫痫是否会影响海马区以外的其他区域，以及 SV2A 表达是否永久性降低或随时间变化而调节。在这项研究中，我们通过腹腔注射氯化锂-匹罗卡品诱导成年雌性大鼠全身性癫痫持续状态（SE）。所有经历 SE 的动物在治疗后不同时间点收集大脑。放射性示踪剂 [C]-UCB-J 与 SV2A 具有高亲和力，已被用于体内成像，作为突触密度的 a 型标志物。在这里，我们通过半定量放射自显影确定大脑皮层、海马体、丘脑和下丘脑以及皮质亚区的 Tritiated UCB-J 结合水平。在 SE 后的头几天，大脑皮层和海马体中观察到 SV2A 结合能力显著且高度降低，但丘脑和下丘脑则没有。在海马体和梨状皮质中，与其他皮质亚区相比，降低幅度更大，发生时间更早。有趣的是，在所有检查的区域中，SE 后 12 周结合能力恢复到对照水平，与慢性癫痫期相当。这些数据表明，氯化锂-匹罗卡品诱导的癫痫发生涉及到突触的丢失和获得，且具有时间依赖性。
