School of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir James Black Building, Glasgow, G12 8QQ, UK.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.
Commun Biol. 2023 May 24;6(1):557. doi: 10.1038/s42003-023-04891-2.
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.
自闭症谱系障碍在男性中更为常见，且具有重要的遗传成分。特别是染色体 16p11.2 缺失，与自闭症存在强烈的遗传风险，但它们的神经生物学影响特征较差，特别是在整合系统水平上。在这里，我们展示了复制这种缺失的小鼠（16p11.2 DEL 小鼠）具有降低的 GABA 能中间神经元基因表达（眶额皮质中的 Parvalbumin mRNA 减少，顶叶和岛叶皮质以及内侧隔核中的 Gad67 mRNA 减少）。内侧隔核的代谢活性增加，其传出靶标：乳头部和（仅雄性）下托。眶额皮质、岛叶和听觉皮质之间以及隔核和海马/下托之间的功能连接发生改变。与这种电路功能障碍一致，16p11.2 DEL 小鼠表现出的条件性恐惧前抑制减少，但在注意力连续测试中的表现增强。自闭症谱系障碍的一级患者在同等的人类测试中也表现出类似的表现增强，这与顶叶、岛叶-眶额皮质和隔核-下托功能障碍有关。这些数据表明，自闭症中前注意和注意力变化的原因是皮质和隔核 GABA 能功能障碍以及由此产生的连接变化。
