University of North Carolina, Chapel Hill, NC 27599-7545, USA.
Neuron. 2012 Jun 7;74(5):793-800. doi: 10.1016/j.neuron.2012.03.036.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele of UBE3A. AS model mice, which carry a maternal Ube3a null mutation (Ube3a(m-/p+)), recapitulate major features of AS in humans, including enhanced seizure susceptibility. Excitatory neurotransmission onto neocortical pyramidal neurons is diminished in Ube3a(m-/p+) mice, seemingly at odds with enhanced seizure susceptibility. We show here that inhibitory drive onto neocortical pyramidal neurons is more severely decreased in Ube3a(m-/p+) mice. This inhibitory deficit follows the loss of excitatory inputs and appears to arise from defective presynaptic vesicle cycling in multiple interneuron populations. In contrast, excitatory and inhibitory synaptic inputs onto inhibitory interneurons are largely normal. Our results indicate that there are neuron type-specific synaptic deficits in Ube3a(m-/p+) mice despite the presence of Ube3a in all neurons. These deficits result in excitatory/inhibitory imbalance at cellular and circuit levels and may contribute to seizure susceptibility in AS.
天使综合征（AS）是一种由 UBE3A 母源性等位基因缺失引起的神经发育障碍。携带母源性 Ube3a 缺失突变（Ube3a(m-/p+)）的 AS 模型小鼠 recapitulates AS 的主要特征，包括增强的癫痫易感性。在 Ube3a(m-/p+)小鼠中，兴奋性神经传递到新皮层锥体神经元减少，这似乎与增强的癫痫易感性不一致。我们在这里表明，Ube3a(m-/p+)小鼠的新皮层锥体神经元抑制性驱动更严重减少。这种抑制缺陷发生在兴奋性输入丧失之后，似乎源于多种中间神经元群体中缺陷的突触小泡循环。相比之下，兴奋性和抑制性突触输入到抑制性中间神经元基本正常。我们的结果表明，尽管所有神经元中都存在 Ube3a，但 Ube3a(m-/p+)小鼠中存在神经元类型特异性的突触缺陷。这些缺陷导致细胞和电路水平的兴奋性/抑制性失衡，可能导致 AS 中的癫痫易感性。
