Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic Inputs.
Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic Inputs.
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DOI：
10.3389/fnmol.2018.00380
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发表时间：
2018
影响因子：
4.8
通讯作者：
Molchanova SM
中科院分区：
文献类型：
--
作者：
Comhair J;Devoght J;Morelli G;Harvey RJ;Briz V;Borrie SC;Bagni C;Rigo JM;Schiffmann SN;Gall D;Brône B;Molchanova SM
含有α2亚基的甘氨酸受体（Glycine receptor, GlyRs）在发育中的大脑中高度表达，调节神经元的迁移和成熟，促进自发网络活动和突触连接的后续发展。GLRA2的突变与自闭症谱系障碍有关，但其潜在的病理生理学尚未被描述。在这里，我们使用glra2敲除小鼠，发现glyr依赖于新生儿背纹状体中棘神经元（MSNs）的自发活动和传入谷氨酸神经支配的成熟。我们的数据表明，功能性GlyRs在1周龄小鼠的msn中高度表达，但它们不产生内源性氯化物介导的强电或相电流。尽管如此，敲除Glra2严重影响动作电位的形状，并损害msn中微型AMPA受体介导电流的自发活性和频率。自发性活动和谷氨酸信号传导的减少可以归因于观察到的新生儿行为表型的变化，如超声发声和翻正反射。在glra2敲除的成年动物中，msn中的谷氨酸能突触在功能上仍然不发达。谷氨酸能突触数量和突触前释放概率不受影响，但突触后AMPA受体数量减少。这种缺陷是神经回路发育受损的结果，因为士的宁对成年msn中GlyRs的急性抑制并不影响谷氨酸突触的特性。总之，这些结果表明，glyr介导的信号传导支持新生儿自发的MSN活动，因此，促进了MSN上谷氨酸能突触的功能成熟。所描述的机制可能揭示glra2相关自闭症谱系障碍病例的病理生理机制。
Glycine receptors (GlyRs) containing the α2 subunit are highly expressed in the developing brain, where they regulate neuronal migration and maturation, promote spontaneous network activity and subsequent development of synaptic connections. Mutations in GLRA2 are associated with autism spectrum disorder, but the underlying pathophysiology is not described yet. Here, using Glra2-knockout mice, we found a GlyR-dependent effect on neonatal spontaneous activity of dorsal striatum medium spiny neurons (MSNs) and maturation of the incoming glutamatergic innervation. Our data demonstrate that functional GlyRs are highly expressed in MSNs of one-week-old mice, but they do not generate endogenous chloride-mediated tonic or phasic current. Despite of that, knocking out the Glra2 severely affects the shape of action potentials and impairs spontaneous activity and the frequency of miniature AMPA receptor-mediated currents in MSNs. This reduction in spontaneous activity and glutamatergic signaling can attribute to the observed changes in neonatal behavioral phenotypes as seen in ultrasonic vocalizations and righting reflex. In adult Glra2-knockout animals, the glutamatergic synapses in MSNs remain functionally underdeveloped. The number of glutamatergic synapses and release probability at presynaptic site remain unaffected, but the amount of postsynaptic AMPA receptors is decreased. This deficit is a consequence of impaired development of the neuronal circuitry since acute inhibition of GlyRs by strychnine in adult MSNs does not affect the properties of glutamatergic synapses. Altogether, these results demonstrate that GlyR-mediated signaling supports neonatal spontaneous MSN activity and, in consequence, promotes the functional maturation of glutamatergic synapses on MSNs. The described mechanism might shed light on the pathophysiological mechanisms in GLRA2-linked autism spectrum disorder cases.
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影响因子：
16.2
作者：
Berry KP;Nedivi E
通讯作者：
Nedivi E
影响因子：
25
作者：
Chen, Yi-Chuan;Kuo, Hsiao-Ying;Bornschein, Ulrich;Takahashi, Hiroshi;Chen, Shih-Yun;Lu, Kuan-Ming;Yang, Hao-Yu;Chen, Gui-May;Lin, Jing-Ruei;Lee, Yi-Hsin;Chou, Yun-Chia;Cheng, Sin-Jhong;Chien, Cheng-Ting;Enard, Wolfgang;Hevers, Wulf;Paeaebo, Svante;Graybiel, Ann M.;Liu, Fu-Chin
通讯作者：
Liu, Fu-Chin
DOI：
10.1073/pnas.94.13.7070
发表时间：
1997-06-24
影响因子：
11.1
作者：
Ehrengruber, MU;Doupnik, CA;Davidson, N
通讯作者：
Davidson, N
影响因子：
5.1
作者：
Cherubini, Enrico;Griguoli, Marilena;Lagostena, Laura
通讯作者：
Lagostena, Laura
影响因子：
16.2
作者：
Fucile, S;De Saint Jan, D;Bregestovski, P
通讯作者：
Bregestovski, P