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Precise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics analysis reveals that the neuronal USP7 interactome is enriched for proteins implicated in neurodevelopmental disorders and specifically identifies the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.

Background and Objectives: Advanced diffusion-weighted MRI (DWI) modeling, such as diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI), may help guide rehabilitation strategies after surgical decompression for cervical spondylotic myelopathy (CSM). Currently, however, postoperative DWI is difficult to interpret, owing to signal distortions from spinal instrumentation. Therefore, we examined the relationship between postoperative DTI/DBSI-extracted from the rostral C3 spinal level-and clinical outcome measures at 2-year follow-up after decompressive surgery for CSM., Methods: Fifty patients with CSM underwent complete clinical and DWI evaluation-followed by DTI/DBSI analysis-at baseline and 2-year follow-up. Clinical outcomes included the modified Japanese Orthopedic Association score and comprehensive patient-reported outcomes. DTI metrics included apparent diffusion coefficient, fractional anisotropy, axial diffusivity, and radial diffusivity. DBSI metrics evaluated white matter tracts through fractional anisotropy, fiber fraction, axial diffusivity, and radial diffusivity as well as extra-axonal pathology through restricted and nonrestricted fraction. Cross-sectional Spearman's correlations were used to compare postoperative DTI/DBSI metrics with clinical outcomes., Results: Twenty-seven patients with CSM, including 15, 7, and 5 with mild, moderate, and severe disease, respectively, possessed complete baseline and postoperative DWI scans. At 2-year follow-up, there were 10 significant correlations among postoperative DBSI metrics and postoperative clinical outcomes compared with 3 among postoperative DTI metrics. Of the 13 significant correlations, 7 involved the neck disability index (NDI). The strongest relationships were between DBSI axial diffusivity and NDI (r = 0.60, P < .001), DBSI fiber fraction and NDI (rs = -0.58, P < .001), and DBSI restricted fraction and NDI (rs = 0.56, P < .001). The weakest correlation was between DTI apparent diffusion coefficient and NDI (r = 0.35, P = .02)., Conclusion: Quantitative measures of spinal cord microstructure after surgery correlate with postoperative neurofunctional status, quality of life, and pain/disability at 2 years after decompressive surgery for CSM. In particular, DBSI metrics may serve as meaningful biomarkers for postoperative disease severity for patients with CSM., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)