Yoo Taesun, Joshi Shambhu, Prajapati Sanjaya, Cho Yi Sul, Kim Jinkyeong, Park Pil-Hoon, Bae Yong Chul, Kim Eunjoon, Kim Soo Young
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea.
College of Pharmacy, Yeungnam University, Gyeongsan, South Korea.
Front Mol Neurosci. 2022 Jul 28;15:938590. doi: 10.3389/fnmol.2022.938590. eCollection 2022.
Genetic variations resulting in the loss of function of the discs large homologs (DLG2)/postsynaptic density protein-93 (PSD-93) gene have been implicated in the increased risk for schizophrenia, intellectual disability, and autism spectrum disorders (ASDs). Previously, we have reported that mice lacking exon 14 of the gene ( mice) display autistic-like behaviors, including social deficits and increased repetitive behaviors, as well as suppressed spontaneous excitatory postsynaptic currents in the striatum. However, the neural substrate underpinning such aberrant synaptic network activity remains unclear. Here, we found that the corticostriatal synaptic transmission was significantly impaired in mice, which did not seem attributed to defects in presynaptic releases of cortical neurons, but to the reduced number of functional synapses in the striatum, as manifested in the suppressed frequency of miniature excitatory postsynaptic currents in spiny projection neurons (SPNs). Using transmission electron microscopy, we found that both the density of postsynaptic densities and the fraction of perforated synapses were significantly decreased in the dorsolateral striatum. The density of dendritic spines was significantly reduced in striatal SPNs, but notably, not in the cortical pyramidal neurons of mice. Furthermore, a DLG2/PSD-93 deficiency resulted in the compensatory increases of DLG4/PSD-95 and decreases in the expression of TrkA in the striatum, but not particularly in the cortex. These results suggest that striatal dysfunction might play a role in the pathology of psychiatric disorders that are associated with a disruption of the gene.
导致盘状大同源物（DLG2）/突触后致密蛋白93（PSD - 93）基因功能丧失的基因变异与精神分裂症、智力障碍和自闭症谱系障碍（ASD）的风险增加有关。此前，我们报道过缺乏该基因第14外显子的小鼠（ 小鼠）表现出自闭症样行为，包括社交缺陷和重复行为增加，以及纹状体中自发兴奋性突触后电流受到抑制。然而，支撑这种异常突触网络活动的神经基质仍不清楚。在这里，我们发现 小鼠的皮质纹状体突触传递明显受损，这似乎并非归因于皮质神经元突触前释放的缺陷，而是由于纹状体中功能性突触数量减少，表现为棘状投射神经元（SPN）中微小兴奋性突触后电流频率受到抑制。通过透射电子显微镜，我们发现 小鼠背外侧纹状体中突触后致密物的密度和穿孔突触的比例均显著降低。纹状体SPN中树突棘的密度显著降低，但值得注意的是，在 小鼠的皮质锥体神经元中并非如此。此外，DLG2/PSD - 93缺乏导致纹状体中DLG4/PSD - 95的代偿性增加以及TrkA表达的降低，但在皮质中并非如此。这些结果表明，纹状体功能障碍可能在与该基因破坏相关的精神疾病病理学中起作用。
