F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Neural Control of Movement Lab, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
Mol Psychiatry. 2024 Jun;29(6):1698-1709. doi: 10.1038/s41380-023-01962-y. Epub 2023 Feb 3.
Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD.
功能和结构连接的改变在神经发育障碍（NDD）的短程和长程投射中都有报道。胼胝体投射神经元（CPN）是大脑中主要的长程投射之一，对于高级认知功能和灵活性尤为重要。然而，在 NDD 中，大脑两半球间连接改变与认知缺陷之间是否存在因果关系仍不清楚。在这里，我们专注于 CDKL5 缺乏症（CDD），这是一种由 X 连锁周期蛋白依赖性激酶样 5 （CDKL5）基因突变引起的严重神经发育障碍。我们通过静息态功能磁共振成像（rs-fMRI）分析发现，成年雄性和雌性 CDKL5 缺陷型小鼠的同型大脑两半球间连接性和高级认知区域的功能连接性增加。这伴随着扣带皮层中胼胝体突触输入的增加和局部突触连接的减少，提示兴奋性突触发育受损和 CDKL5 在兴奋性神经元亚型中发挥不同的作用。这些缺陷与 CDKL5 KO 小鼠的显著认知障碍有关。选择性删除 CPN 中最大的亚型中的 CDKL5 同样导致功能胼胝体输入增加，但并未显著改变皮质内扣带网络。值得注意的是，这种胼胝体特异性的改变足以导致认知缺陷。最后，当 CDKL5 仅在这种 CPN 亚型中选择性重新表达时，在其他 CDKL5 缺陷型小鼠中，足以防止 CDKL5 突变体的认知障碍。总之，这些结果揭示了 CDKL5 的一个新作用，表明它对于 CPN 连接和认知功能和灵活性的正常运作是必要和充分的，并进一步验证了在 NDD 模型中 CPN 功能障碍与认知障碍之间的因果关系。
