Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism
Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism
复制标题
DOI：
10.1073/pnas.1222803110
复制
发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Zukin, R. Suzanne
中科院分区：
文献类型：
--
作者：
Takeuchi, Koichi;Gertner, Michael J.;Zukin, R. Suzanne
肌醇磷脂信号系统是神经发育、细胞存活和可塑性的重要调节因子。10号染色体上缺失的磷酸酶和张力蛋白同源物(PTEN)负向调节磷脂酰肌醇3-激酶信号和下游靶标。在NSE-CRE Pten条件基因敲除小鼠中，Pten在齿状回和海马CA3区锥体神经元的颗粒细胞中被消融，而不是CA1，它概括了PTEN基因突变失活的人类的许多症状，包括齿状回进行性肥大以及基于河马校园的社会和认知行为缺陷。然而，在这种临床相关的Pten失活小鼠模型中，Pten丢失对活性依赖的突触可塑性的影响尚不清楚。在这里，我们证明了两种依赖于磷脂酰肌醇3-激酶和蛋白质合成的突触可塑性形式，theta Burst诱导的长期增强和代谢性谷氨酸受体(MGluR)依赖的长期抑制，在可见的形态异常发生之前，在年轻的NSE-CRE Pten条件性基因敲除小鼠的内侧穿孔路径到齿状回突触上受到异常调节。相反，在这个年龄段的CA3-CA1锥体细胞突触中，长时程增强和依赖mGluR的长时程抑制是正常的。我们的结果表明，齿状颗粒细胞中Pten的缺失调节突触可塑性，这一缺陷可能是在患有Pten失活突变和潜在的其他自闭症谱系障碍的人类中观察到的异常社会和认知行为的原因。
The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippo-campus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase- and protein synthesis-dependent forms of synaptic plasticity, theta burst-induced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young Nse-Cre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.