Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication.
Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication.
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DOI：
10.1186/2040-2392-1-15
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发表时间：
2010-12-17
期刊：
影响因子：
6.2
通讯作者：
Buxbaum JD
中科院分区：
文献类型：
--
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
SHANK 3是突触后致密物（PSD）核心中的蛋白质，并且在将许多关键功能元件募集至PSD和突触中具有关键作用，包括α-氨基-3-羟基-5-甲基-4-异恶唑-丙酸（AMPA）、代谢型谷氨酸（mGlu）和N-甲基-D-天冬氨酸（NMDA）谷氨酸受体的组分以及细胞骨架元件。SHANK 3基因功能性拷贝的丢失导致22 q13缺失综合征和/或自闭症谱系障碍的神经行为表现。本研究的目的是检查全长Shank 3单倍不足对小鼠的影响，重点是突触发育，传递和可塑性，以及社会行为，作为理解人类SHANK 3单倍不足的模型。我们使用了具有靶向破坏Shank 3的小鼠，其中编码锚蛋白重复结构域的外显子被删除，全长Shank 3的表达被破坏。我们采用膜片钳全细胞记录、双光子延时成像和细胞外记录场兴奋性突触后电位等方法研究了突触传递和可塑性。我们还研究了密度的GluR 1免疫反应斑点在CA 1层辐射和进行评估的社会行为。在Shank 3杂合子小鼠中，海马CA 1区锥体神经元的微型兴奋性突触后电流振幅降低，急性海马切片中Schaffer侧支-CA 1突触的输入-输出（I/O）关系显著降低;这两项研究结果均表明基础神经传递减少。使用特异性抑制剂的研究表明，基础传输的减少反映了AMPA受体介导的传输减少。这进一步得到了放射层中GluR 1免疫反应性斑点数量减少的观察结果的支持。在Shank 3杂合子小鼠中，θ-爆发配对（TBP）或高频刺激诱导的长时程增强（LTP）受损，而长时程抑郁（LTD）无显著变化。与LTP结果一致，在TBP诱导的LTP后，在对照小鼠中观察到脊柱的持续扩张;然而，在Shank 3杂合子小鼠中仅观察到短暂的脊柱扩张。与野生型同窝对照组相比，雄性Shank 3杂合子在与发情期雌性小鼠的相互作用中表现出较少的社会嗅探和较少的超声波发声。我们记录了突触功能和可塑性的特定缺陷，沿着Shank 3杂合子小鼠的相互社会互动减少。我们的研究结果与Shank 3单倍不足中突触发育和功能的改变一致，突出了Shank 3在突触功能中的重要性，并支持突触功能缺陷与神经发育障碍之间的联系。我们在Shank 3杂合子小鼠中观察到的减少的线粒体能传递代表了Shank 3-单倍不足综合征的一个有趣的治疗靶点。
SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with θ-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes.
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DOI：
10.1523/jneurosci.3145-08.2008
发表时间：
2008-09-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bozdagi O;Rich E;Tronel S;Sadahiro M;Patterson K;Shapiro ML;Alberini CM;Huntley GW;Salton SR
通讯作者：
Salton SR
影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
影响因子：
16.2
作者：
Holtmaat, AJGD;Trachtenberg, JT;Svoboda, K
通讯作者：
Svoboda, K
影响因子：
56.9
作者：
Huber, KM;Kayser, MS;Bear, MF
通讯作者：
Bear, MF
影响因子：
5.3
作者：
Hung, Albert Y.;Futai, Kensuke;Sheng, Morgan
通讯作者：
Sheng, Morgan