Alterations of GABAergic Neuron-Associated Extracellular Matrix and Synaptic Responses in Gad1-Heterozygous Mice Subjected to Prenatal Stress.
Alterations of GABAergic Neuron-Associated Extracellular Matrix and Synaptic Responses in Gad1-Heterozygous Mice Subjected to Prenatal Stress.
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DOI：
10.3389/fncel.2018.00284
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发表时间：
2018
影响因子：
5.3
通讯作者：
Fukuda A
中科院分区：
文献类型：
--
作者：
Wang T;Sinha AS;Akita T;Yanagawa Y;Fukuda A
暴露于产前应激（PS）和编码GABA合成酶谷氨酸脱羧酶（GAD）67的Gad 1突变是与内侧前额叶皮层（mPFC）中小清蛋白（PV）阳性GABA能中间神经元异常相关的精神疾病的主要风险因素。细胞外基质（ECM）糖蛋白的表达减少也有报道，在这些疾病的患者，提出了ECM异常可能在其发病机制中发挥作用的可能性。为了阐明由基因-环境相互作用诱导的ECM的病理生理变化，我们检查了从胚胎第15.0天至17.5天经受PS的杂合GAD 67-GFP（敲入KI; GAD 67 +/GFP）小鼠。与我们之前的研究一致，我们证实了出生后GAD 67 +/GFP小鼠PS的mPFC中PV神经元密度的降低，这与被神经元周网（PNN）包围的PV神经元密度的降低同时发生，PNN是一种对PV神经元的成熟、突触稳定和可塑性非常重要的专门ECM。抑制性突触周围ECM中α-肌营养不良蛋白聚糖（α-DG）及其推定介导因子Fktn（Fktn）的糖基化也被认为有助于疾病的发展。我们发现GAD 67 +/GFP小鼠PS后糖基化的α-DG和Fktn的mRNA水平均降低。在GAD 67 +/GFP幼稚小鼠或野生型（GAD 67 +/+）PS小鼠中未检测到这些变化，表明PS和Gad 1基因表达降低是这些变化的先决条件。当通过第V层锥体神经元中诱发的抑制性突触后电流（eIPSC）评估GAD 67 +/GFP小鼠与PS的mPFC中的中间神经元的功能时，我们发现eIPSC事件的阈值刺激强度降低，并且eIPSC幅度增加而不改变成对脉冲比（PPR）。此外，eIPSC的衰减速率也减慢。与eIPSC一致，自发IPSC（sIPSC）振幅、频率和衰减τ改变。因此，我们的研究表明，基因-环境相互作用介导的ECM的改变可能与增强和延长GABA的作用，以补偿PV神经元密度的降低有关。这可能是精神病患者mPFC兴奋/抑制失衡的原因之一。
Exposure to prenatal stress (PS) and mutations in Gad1, which encodes GABA synthesizing enzyme glutamate decarboxylase (GAD) 67, are the primary risk factors for psychiatric disorders associated with abnormalities in parvalbumin (PV)-positive GABAergic interneurons in the medial prefrontal cortex (mPFC). Decreased expression of extracellular matrix (ECM) glycoproteins has also been reported in patients with these disorders, raising the possibility that ECM abnormalities may play a role in their pathogenesis. To elucidate pathophysiological changes in ECM induced by the gene–environment interaction, we examined heterozygous GAD67-GFP (Knock-In KI; GAD67+/GFP) mice subjected to PS from embryonic day 15.0 to 17.5. Consistent with our previous study, we confirmed a decrease in the density of PV neurons in the mPFC of postnatal GAD67+/GFP mice with PS, which was concurrent with a decrease in density of PV neurons surrounded by perineuronal nets (PNNs), a specialized ECM important for the maturation, synaptic stabilization and plasticity of PV neurons. Glycosylation of α-dystroglycan (α-DG) and its putative mediator fukutin (Fktn) in the ECM around inhibitory synapses has also been suggested to contribute to disease development. We found that both glycosylated α-DG and the mRNA level of Fktn were reduced in GAD67+/GFP mice with PS. None of these changes were detected in GAD67+/GFP naive mice or wild type (GAD67+/+) mice with PS, suggesting that both PS and reduced Gad1 gene expression are prerequisites for these changes. When assessing the function of interneurons in the mPFC of GAD67+/GFP mice with PS through evoked inhibitory post-synaptic currents (eIPSCs) in layer V pyramidal neurons, we found that the threshold stimulus intensity for eIPSC events was reduced and that the eIPSC amplitude was increased without changes in the paired-pulse ratio (PPR). Moreover, the decay rate of eIPSCs was also slowed. In line with eIPSC, spontaneous IPSC (sIPSC) amplitude, frequency and decay tau were altered. Thus, our study suggests that alterations in the ECM mediated by gene-environment interactions might be linked to the enhanced and prolonged GABA action that compensates for the decreased density of PV neurons. This might be one of the causes of the excitatory/inhibitory imbalance in the mPFC of psychiatric patients.
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影响因子：
4.8
作者：
Ansari, Amir Mehdi;Ahmed, A. Karim;Matsangos, Aerielle E.;Lay, Frank;Born, Louis J.;Marti, Guy;Harmon, John W.;Sun, Zhaoli
通讯作者：
Sun, Zhaoli
影响因子：
4.9
作者：
Gogolla, Nadine;LeBlanc, Jocelyn J.;Quast, Kathleen B.;Sudhof, Thomas C.;Fagiolini, Michela;Hensch, Takao K.
通讯作者：
Hensch, Takao K.
DOI：
10.1083/jcb.122.4.809
发表时间：
1993-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ervasti JM;Campbell KP
通讯作者：
Campbell KP
DOI：
10.1176/appi.ajp.2015.14081031
发表时间：
2015-11-01
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Frankle WG;Cho RY;Prasad KM;Mason NS;Paris J;Himes ML;Walker C;Lewis DA;Narendran R
通讯作者：
Narendran R
影响因子：
7.6
作者：
Enwright, John F.;Sanapala, Sowmya;Lewis, David A.
通讯作者：
Lewis, David A.