16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability.
16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability.
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DOI：
10.1038/s42003-023-04891-2
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发表时间：
2023-05-24
影响因子：
5.9
通讯作者：
Dawson, Neil
中科院分区：
文献类型：
--
作者：
Openshaw, Rebecca L.;Thomson, David M.;Bristow, Greg C.;Mitchell, Emma J.;Pratt, Judith A.;Morris, Brian J.;Dawson, Neil
自闭症谱系障碍在男性中更常见，并且具有相当大的遗传成分。特别是染色体16p11.2缺失对自闭症具有很强的遗传风险，但其神经生物学影响的特征很差，特别是在综合系统水平上。在这里，我们发现，复制这种缺失的小鼠（16 p11.2 DEL小鼠）具有减少的GABA能中间神经元基因表达（减少的小白蛋白mRNA在眶额皮质，和男性特异性减少Gad 67 mRNA在顶叶和岛叶皮质和内侧隔）。内侧隔及其传出靶点：乳头体和（仅雄性）下托的代谢活性增加。眶额、岛叶和听觉皮层之间以及隔和海马/下托之间的功能连接发生改变。与这种电路功能障碍相一致，16p11.2 DEL小鼠表现出减少前脉冲抑制，但在注意力能力的连续性能测试中表现增强。1级自闭症患者在同等的人类测试中表现出类似的提高表现，也与顶叶，岛眶额和隔下托功能障碍有关。这些数据暗示皮质和隔GABA能功能障碍，以及由此产生的连接变化，是自闭症前注意力和注意力变化的原因。16p11.2缺失的半合子小鼠表现出局部功能性连接障碍和GABA能基因表达改变，暗示GABA能功能障碍和自闭症谱系障碍注意力变化中的连接变化。
Autism spectrum disorders are more common in males, and have a substantial genetic component. Chromosomal 16p11.2 deletions in particular carry strong genetic risk for autism, yet their neurobiological impact is poorly characterised, particularly at the integrated systems level. Here we show that mice reproducing this deletion (16p11.2 DEL mice) have reduced GABAergic interneuron gene expression (decreased parvalbumin mRNA in orbitofrontal cortex, and male-specific decreases in Gad67 mRNA in parietal and insular cortex and medial septum). Metabolic activity was increased in medial septum, and in its efferent targets: mammillary body and (males only) subiculum. Functional connectivity was altered between orbitofrontal, insular and auditory cortex, and between septum and hippocampus/subiculum. Consistent with this circuit dysfunction, 16p11.2 DEL mice showed reduced prepulse inhibition, but enhanced performance in the continuous performance test of attentional ability. Level 1 autistic individuals show similarly heightened performance in the equivalent human test, also associated with parietal, insular-orbitofrontal and septo-subicular dysfunction. The data implicate cortical and septal GABAergic dysfunction, and resulting connectivity changes, as the cause of pre-attentional and attentional changes in autism. Mice hemizygous for the 16p11.2 deletion exhibit localized functional dysconnectivity and altered GABAergic gene expression, implicating GABAergic dysfunction and resulting connectivity changes in attentional changes in autism spectrum disorder.
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影响因子：
8.8
作者：
Bristow, Greg C.;Thomson, David M.;Morris, Brian J.
通讯作者：
Morris, Brian J.
成人自闭症谱系障碍的额叶网络。
DOI：
10.1093/brain/awv351
发表时间：
2016-02
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Catani M;Dell'Acqua F;Budisavljevic S;Howells H;Thiebaut de Schotten M;Froudist-Walsh S;D'Anna L;Thompson A;Sandrone S;Bullmore ET;Suckling J;Baron-Cohen S;Lombardo MV;Wheelwright SJ;Chakrabarti B;Lai MC;Ruigrok AN;Leemans A;Ecker C;Consortium MA;Craig MC;Murphy DG
通讯作者：
Murphy DG
影响因子：
11
作者：
Di Martino, A.;Yan, C-G;Li, Q.;Denio, E.;Castellanos, F. X.;Alaerts, K.;Anderson, J. S.;Assaf, M.;Bookheimer, S. Y.;Dapretto, M.;Deen, B.;Delmonte, S.;Dinstein, I.;Ertl-Wagner, B.;Fair, D. A.;Gallagher, L.;Kennedy, D. P.;Keown, C. L.;Keysers, C.;Lainhart, J. E.;Lord, C.;Luna, B.;Menon, V.;Minshew, N. J.;Monk, C. S.;Mueller, S.;Mueller, R. A.;Nebel, M. B.;Nigg, J. T.;O'Hearn, K.;Pelphrey, K. A.;Peltier, S. J.;Rudie, J. D.;Sunaert, S.;Thioux, M.;Tyszka, J. M.;Uddin, L. Q.;Verhoeven, J. S.;Wenderoth, N.;Wiggins, J. L.;Mostofsky, S. H.;Milham, M. P.
通讯作者：
Milham, M. P.
影响因子：
11.3
作者：
Cheng, Chia-Hsiung;Chang, Pei-Ying S.;Liu, Chia-Yih
通讯作者：
Liu, Chia-Yih
影响因子：
2.6
作者：
Caron, MJ;Mottron, L;Chouinard, S
通讯作者：
Chouinard, S