Significance: FOXP1 haploinsufficiency underlies cognitive and motor impairments in individuals with FOXP1 syndrome. Here, we show that mice lacking one Foxp1 copy exhibit similar behavioral deficits, which may be caused by striatal dysfunction. Indeed, Foxp1 ^+/− striatal medium spiny neurons display reduced neurite branching, and we show altered mitochondrial biogenesis and dynamics; increased mitophagy; reduced mitochondrial membrane potential, structure, and motility; and elevated oxygen species in the striatum of these animals. As FOXP1 is highly conserved, our data strongly suggest that mitochondrial dysfunction and excessive oxidative stress contribute to the motor and cognitive impairments seen in individuals with FOXP1 syndrome. Thus, mitochondrial homeostasis is critical for normal development and can explain deficits in neurodevelopmental disorders.

Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1^+/− mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1^+/− hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1^+/− mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.

Microglia, the brain’s resident macrophages, arise from yolk sac hematopoietic progenitor cells (HPCs) that migrate into the brain during early embryonic development and differentiate in response to microenvironment-specific signals. The resulting spatial and stage-specific programs of gene expression enable microglia to function as key modulators of diverse homeostatic processes that include synaptic pruning, myelination, and neurogenesis throughout the lifespan. Dysregulation of these core microglia functions has been linked to numerous neurodevelopmental and neurodegenerative diseases. Although normally a closed niche, studies in mice indicate that peripheral monocytes, originating from hematopoietic stem cells (HSCs), can infiltrate the brain in circumstances in which the blood brain barrier is disrupted, with context-dependent protective or detrimental consequences. A major unanswered question with significant implications for therapy of CNS diseases driven by microglia dysfunction is the extent to which human HSC-derived cells can adopt microglia-like phenotypes that would allow them to restore brain homeostasis by replacement of pathologic HPC-derived microglia. To address this question, we directly compared the differentiation potential of primary human microglia, human iPSC-derived HPCs and human HSCs in the brain utilizing a murine xenotransplantation model. HSCs and monocytes were capable of differentiating into microglia like cells in this model, they also acquired a strong interferon, phagocytic, and antigen presenting phenotype distinct from engrafted primary human microglia and HPC-derived cells. Analyses of the epigenetic landscapes of the engrafted HPC and HSC-derived cells enabled identification of the transcription factors networks underlying ontogeny-specific brain myeloid fates. Ultimately, human peripheral myeloid cells in the CNS led to astrogliosis, myelin fragmentation and synaptic loss. These findings reveal transcriptional network differences influenced by ontogeny, and together with the accompanying study by Davtvan and colleagues provide critical insights for developing human microglial or bone marrow transplant-based therapies for CNS disorders.

Background. Recent studies have shown that Ras‐like without CAAX2 (RIT2) polymorphism is a susceptible factor for Parkinson’s disease (PD) and autism spectrum disorder (ASD). SNP rs12456492 and rs16976358 show the emerging evidence of increased risk of PD and ASD, respectively. A meta‐analysis examining the relationship between rs12456492 and PD was reported, but the association between rs16976358 and ASD has not been investigated. Methods. We searched literature from the databases PubMed, Embase, Google Scholar, ScienceDirect, EBSCOhost, OVID, Web of Science, and Wiley up to February 2021. Three studies including 1160 ASD cases and 1367 controls were eventually enrolled in the meta‐analysis based on strict inclusion and exclusion criteria. Results. All genetics models indicate a significant association between rs16976358 polymorphism and ASD susceptibility (C vs. T: p = 0.001; CC vs. TT: p = 0.001; CT vs. TT: p = 0.009; CC+CT vs. TT: p = 0.001; CC vs. CT+TT: p = 0.001; TT+CC vs. CT: p = 0.013). The results of sensitivity analysis and publication bias of Begg’s and Egger’s tests were stable in the models of allele (C vs. T), codominant (CC vs. TT), dominant (CC+CT vs. TT), and recessive (CC vs. CT+TT). Conclusions. Our meta‐analysis exhibits that the allele C, CC, and CT genotyping of rs16976358 suggest the risk for ASD, but additional studies using a large sample size and ethnically diverse populations need to be included in the future.