Department of Molecular and Systems Biology, Dartmouth Geisel School of Medicine, Hanover, NH, 03755, USA.
Department of Neurosciences, Cleveland Clinic, Cleveland, OH, 44195, USA.
Mol Psychiatry. 2019 Nov;24(11):1627-1640. doi: 10.1038/s41380-019-0412-6. Epub 2019 Apr 9.
Pten mutations are associated with autism spectrum disorder. Pten loss of function in neurons increases excitatory synaptic connectivity, contributing to an imbalance between excitation and inhibition. We aimed to determine whether Pten loss results in aberrant connectivity in neural circuits. We compared postnatally generated wild-type and Pten knockout granule neurons integrating into the dentate gyrus using a variety of methods to examine their connectivity. We found that postsynaptic Pten loss provides an advantage to dendritic spines in competition over a limited pool of presynaptic boutons. Retrograde monosynaptic tracing with rabies virus reveals that this results in synaptic contact with more presynaptic partners. Using independently excitable opsins to interrogate multiple inputs onto a single neuron, we found that excess connectivity is established indiscriminately from among glutamatergic afferents. Therefore, Pten loss results in inappropriate connectivity whereby neurons are coupled to a greater number of synaptic partners.
PTEN 突变与自闭症谱系障碍有关。神经元中 PTEN 功能丧失会增加兴奋性突触连接，导致兴奋与抑制之间失衡。我们旨在确定 PTEN 缺失是否会导致神经回路连接异常。我们比较了在齿状回中整合的出生后产生的野生型和 Pten 敲除颗粒神经元，使用多种方法来检查它们的连接。我们发现，在与有限数量的突触前末梢竞争中，突触后 PTEN 缺失为树突棘提供了优势。用狂犬病病毒进行逆行单突触追踪表明，这会导致与更多的突触前伙伴建立突触联系。使用可独立激发的光学蛋白来探测单个神经元上的多个输入，我们发现，多余的连接是从谷氨酸能传入中不加区分地建立的。因此，PTEN 缺失导致了不适当的连接，使神经元与更多的突触伙伴耦合。
