PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus.
PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus.
复制标题
DOI：
10.1038/s41598-017-08809-x
复制
发表时间：
2017-08-15
影响因子：
4.6
通讯作者：
Hunt RF
中科院分区：
文献类型：
--
作者：
Dinday MT;Girskis KM;Lee S;Baraban SC;Hunt RF
编码血小板活化因子乙酰水解酶IB亚基α (Pafah1b1)的人类基因的半合子突变，也称为无裂脑-1，可导致经典无裂脑畸形，这是一种严重的皮质发育畸形。患有这种疾病的儿童会出现神经元迁移缺陷、严重智力残疾、顽固性癫痫和早期死亡。虽然许多这些特征可以在Pafah1b1+/−小鼠中重现，但Pafah1b1+/−对单个神经元亚群功能和最终脑回路的影响在很大程度上是未知的。在Pafah1b1+/−小鼠中，年轻的gaba能中间神经元向发育中的海马的切向迁移速度减慢。突变小鼠齿状回小白蛋白和生长抑素阳性中间神经元密度降低，而calretinin中间神经元密度无变化。全细胞膜片钳记录显示Pafah1b1+/−小鼠颗粒细胞的兴奋性突触输入增加，抑制性突触输入减少。突变动物出现自发性电痉挛，以及情境记忆的长期缺陷。我们的研究结果为Pafah1b1+/−小鼠齿状回兴奋性的显著变化提供了证据，这可能导致癫痫或与无脑畸形相关的认知障碍。
Hemizygous mutations in the human gene encoding platelet-activating factor acetylhydrolase IB subunit alpha (Pafah1b1), also called Lissencephaly-1, can cause classical lissencephaly, a severe malformation of cortical development. Children with this disorder suffer from deficits in neuronal migration, severe intellectual disability, intractable epilepsy and early death. While many of these features can be reproduced in Pafah1b1+/− mice, the impact of Pafah1b1+/− on the function of individual subpopulations of neurons and ultimately brain circuits is largely unknown. Here, we show tangential migration of young GABAergic interneurons into the developing hippocampus is slowed in Pafah1b1+/− mice. Mutant mice had a decreased density of parvalbumin- and somatostatin-positive interneurons in dentate gyrus, but no change in density of calretinin interneurons. Whole-cell patch-clamp recordings revealed increased excitatory and decreased inhibitory synaptic inputs onto granule cells of Pafah1b1+/− mice. Mutant animals developed spontaneous electrographic seizures, as well as long-term deficits in contextual memory. Our findings provide evidence of a dramatic shift in excitability in the dentate gyrus of Pafah1b1+/− mice that may contribute to epilepsy or cognitive impairments associated with lissencephaly.
登录
查看更多内容
DOI：
10.1126/science.1247485
发表时间：
2014-02-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lovett-Barron M;Kaifosh P;Kheirbek MA;Danielson N;Zaremba JD;Reardon TR;Turi GF;Hen R;Zemelman BV;Losonczy A
通讯作者：
Losonczy A
DOI：
10.1523/jneurosci.0032-11.2011
发表时间：
2011-05-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hunt RF;Scheff SW;Smith BN
通讯作者：
Smith BN
影响因子：
25
作者：
Hansen, David V.;Lui, Jan H.;Flandin, Pierre;Yoshikawa, Kazuaki;Rubenstein, John L.;Alvarez-Buylla, Arturo;Kriegstein, Arnold R.
通讯作者：
Kriegstein, Arnold R.
影响因子：
34.7
作者：
Ascoli, Giorgio A.;Alonso-Nanclares, Lidia;Anderson, Stewart A.;Barrionuevo, German;Benavides-Piccione, Ruth;Burkhalter, Andreas;Buzsaki, Gyoergy;Cauli, Bruno;DeFelipe, Javier;Fairen, Alfonso;Feldmeyer, Dirk;Fishell, Gord;Fregnac, Yves;Freund, Tamas F.;Gardner, Daniel;Gardner, Esther P.;Goldberg, Jesse H.;Helmstaedter, Moritz;Hestrin, Shaul;Karube, Fuyuki;Kisvarday, Zoltan F.;Lambolez, Bertrand;Lewis, David A.;Marin, Oscar;Markram, Henry;Munoz, Alberto;Packer, Adam;Petersen, Carl C. H.;Rockland, Kathleen S.;Rossier, Jean;Rudy, Bernardo;Somogyi, Peter;Staiger, Jochen F.;Tamas, Gabor;Thomson, Alex M.;Toledo-Rodriguez, Maria;Wang, Yun;West, David C.;Yuste, Rafael
通讯作者：
Yuste, Rafael
影响因子：
5.3
作者：
Ewell, Laura A.;Jones, Mathew V.
通讯作者：
Jones, Mathew V.