We recently identified variants in 10 genes that are members of either the p53 pathway or Fanconi Anemia Complex (FAC), regulators of the DNA repair (DNA damage response; DDR) in 17 cases with Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS) or regression in autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDD). We aimed to identify additional cases with genetic vulnerabilities in DDR and related pathways. Whole exome sequencing (WES) and whole genome sequencing (WGS) data from 32 individuals were filtered and analyzed to identify ultrarare pathogenic or likely pathogenic variants. Variants affecting DDR were found in 14 cases diagnosed with PANS or regression (CUX1, USP45, PARP14, UVSSA, EP300, TREX1, SAMHD1, STK19, MYTl1, TEP1, PIDD1, ADNP, FANCD2, and RAD54L). The CUX1 variant is de novo, as are two cases who had mutations in genes that affect mitochondrial functions that are connected directly or indirectly to mitophagy (PRKN and POLG), which can trigger the same innate immune pathways when disrupted as abnormal DDR. We also found pathogenic or likely pathogenic secondary mutations in several genes that are primarily expressed in the gut that have been implicated in gut microbiome homeostasis (e.g., LGALS4, DUOX2, CCR9). These findings align with previous genetic findings and strengthen the hypothesis that abnormal DDR and mitochondrial dysfunction underly pathogenic processes in neuropsychiatric decompensation. The potential involvement of genetic variants in gut microbiome homeostasis is a novel aspect of our study. Functional characterization of the downstream impact of DDR deficits may point to novel treatment strategies.

According to literature, early stress may lead to a higher susceptibility to the action of various stressors later in life, thus largely contributing to the development of a wide range of affective disorders. Disrupting maternal care is one way to destabilize the environment for pups, which may result in the formation of an altered reaction to acute or moderate stress. In this study, we analyzed the effects of limited bedding and nesting material (LBN) in PND2-PND9 on baseline gene expression in the hippocampus and frontal cortex of 1-month old rats and the expression of the same genes under conditions of 60-minute restraint. Among the analyzed genes, some were associated with glucocorticoids (Nr3c1 and Nr3c2), others with the activation of the immune system (Nfkbia, Ccl2, Il1b, Il6, Tnfα, Cx3cl1, Cx3cr1, and Ncf1), and yet others with the activation of neuronal networks under stress (Cfos, Ier-2). Gene expression was assessed using real-time PCR (RT-PCR). Exposure to LBN during early postnatal life significantly increased baseline expression of the Fos gene in the amygdala of adolescent rats. LBN exposure more slightly affected the expression of other analyzed genes (Nr3c1, Cx3cl1, Ier2, Ncf1) or evoked alterations of their expression in this group only after exposure to acute restraint stress. The hyperglycemic response to acute restraint was attenuated in LBN-exposed animals, while corticosterone levels were comparable to controls. Among the studied genes, the expression of Nfkbia, Il6, and Tnf was primarily influenced by acute restraint stress, independently of LBN history. The amygdala and ventral hippocampus were the brain regions where the expression of the analyzed genes appeared most sensitive to the experimental manipulations. These data indicate that early-life stress induced by LBN leads to a sustained increase in baseline Fos expression in the amygdala and alters the metabolic response to acute stress in adolescence. The findings further suggest that the amygdala and ventral hippocampus are key regions where the expression of a limited set of stress-related genes is modulated by the interplay of early-life adversity and acute stress. This points to a potential role for amygdalar circuits in the altered stress reactivity observed following adverse early-life conditions.

Neonatal rats, but not juvenile rats, show spontaneous hindlimb locomotor recovery after complete thoracic spinal cord transection (SCT). Significant increases in parvalbumin-positive proprioceptive nerve terminals are observed on motoneurons in both neonatal and juvenile rats with SCT compared with intact rats. In the present study, we focused on Chx10-positive V2a interneurons, which partially comprise the central pattern generator, and examined parvalbumin-positive nerve terminals on Chx10 neurons and the perineuronal net formation around these neurons using Wisteria Floribunda agglutinin (WFA) as a marker 2 weeks after SCT on postnatal day 5 (neonatal) or day 20 (juvenile). Rats with CST during the neonatal period had a significantly greater number of parvalbumin-positive terminals on Chx10 neurons compared to age-matched intact rats, whereas no significant difference was detected between rats with SCT during the juvenile period and age-matched intact rats. Chx10 neurons for which ≥50% of the circumference was surrounded by WFA were identified as WFA-positive. The proportion of WFA-positive neurons among Chx10-positive neurons did not differ significantly between neonatal SCT and age-matched intact rats, but was significantly higher in juvenile SCT and age-matched intact rats. These findings suggest that SCT promotes the formation of proprioceptive afferent terminals on Chx10-positive neurons. The significant increase in terminals following SCT in neonatal rats might facilitate spontaneous motor recovery, whereas enhanced perineuronal net formation around Chx10 neurons following juvenile SCT might restrict synaptic formation and impair motor recovery.

In the article "Caffeine as a Treatment for Perinatal Hypoxic-Ischemic Brain Injury: The Potential Risks and Benefits" [Dev Neurosci. 2025; Online ahead of print. https://doi.org/10.1159/000545126] by Zhou et al., the authors noted that there were several errors within their article. The corrections are listed below.In the section "Adenosine and Adenosine Receptors" currently reads, "By contrast, A2 adenosine receptor knockout mice that were subjected to common carotid ligation and hypoxia at P7 had more severe brain injury with worse performance in motor behavioural tests, compared with wild-type mice [30]." Should correctly read, "By contrast, A2A adenosine receptor knockout mice that were subjected to common carotid ligation and hypoxia at P7 had more severe brain injury with worse performance in motor behavioural tests, compared with wild-type mice [30]."Reference 47 was erroneously included and is not an intended citation, this reference should be deleted. Under the subheading, "Caffeine: Perspectives and Future Directions", the following sentences should correctly read:It is unclear why studies in rodents suggest benefit with prophylactic caffeine, before HI, whereas limited benefit with prophylactic caffeine in lambs [39], and deleterious effects of adenosine A1 receptor blockade [20]. Speculatively, this difference may reflect that these rodent studies used inhalational hypoxia and so caffeine may help avoid apnea [48] and so reduce the risk of deep hypoxemia. Regardless of the precise mechanism, these findings strongly suggest that considerable caution is needed before considering human studies.The following two errors table 1 should be corrected. For the study Yang et al., 2022, under key findings was missing before "Microglia M2 polarisation". For the study, Sabir et al., 2023 and in row 8 the study year was corrected to 2023.The corrected table is shown below:Table 1.Summary of preclinical studies on the effects of caffeine for perinatal hypoxic-ischemic brain injuryStudySpecies and ageN per groupInsultDose and timingKey findingsDi Martino et al. [34] (2020)P10 micen = 8-10Common carotid artery ligation and hypoxia (1 h)Caffeine 5 mg/kg, i.p. immediately after HI↓ Grey and white matter lesion size↓ Amoeboid microglia and apoptotic cellsn = 6-8Caffeine started at 6, 12 or 24 h after HINo neuroprotective effectWinerdal et al. [35] (2017)P10 micen = 13-29Common carotid artery ligation and hypoxia (1 h)Caffeine 5 mg/kg i.p. immediately after HI↓ Brain atrophy↑ Time on the rotorod behavioral testPotter et al. [37] (2018)P6 ratsn = 6Common carotid artery ligation and hypoxia (2 h)Caffeine citrate 20 mg/kg i.p. administration immediately after HI↑ Performance in rotarod and water maze behavioral tests↑ Silent gap detection (speech detection)Bernis et al. [38] (2025)P7 ratsn = 5-50Common carotid artery ligation and hypoxia (90 min)Caffeine citrate 15, 20 or 40 mg/kg i.p. administration immediately before HI or 40 mg/kg immediately after HI repeated at 24 and 48 h↓ Brain area loss (greatest effect with 40 mg/kg before HI)↓ Microgliosis (40 mg/kg before HI)n = 14Caffeine citrate 120 mg/kg before HI and at 24 h↑ MortalityYang et al. [33] (2022)P3 ratsn = 6Common carotid artery ligation and hypoxia (2.5 h)Caffeine citrate 20 mg/kg/day, i.p. from day 2-6↓ Ventricle dilation↑ MBP expression↓ NLRP3 inflammasome activation↑ Microglia M2 polarisation↓ Microglial activation and microglia M1 polarizationKilicdag et al. [32] (2014)P7 ratsn = 8Common carotid artery ligation and hypoxia (2 h)Caffeine citrate 20 mg/kg/day, i.p. immediately before HI and at 0, 24, 48 and 72 h after HI↓ Cell loss in hippocampus and cortexAlexander et al. [36] (2013)P7 rats (males only)n = 8-15Common carotid artery ligation and hypoxia (2 h)Caffeine 10 mg/kg i.p. immediately after HIPartially ↑ cortical volume↑ Performance in morris water mazeSabir et al. [39] (2023)P7 ratsn = 12Common carotid artery ligation and hypoxia (1.5 h)Caffeine 40 mg/kg i.p. 1 h before hypoxia and at 24 and 48 h↓ Brain area lossMike et al. [40] (2024)Gestational day 141-143 fetal sheepn = 4-41Umbilical cord occlusion, until the onset of asysole1 g i.v. to ewe before delivery, 20 mg/kg caffeine citrate, 2 doses of 10 mg/kg i.v. at 24 and 48 h (lambs)↔ Hippocampal neuronal survival↓ Neuronal apoptosis hippocampus (CA3 only)↑ Feeding and activity↓ Microgliosisn = 8Caffeine citrate 60 mg/kg i.v. and 30 mg/kg at 24 and 48 h (lambs only)↑ Mortality.

Introduction: Lysophosphatidic acid (LPA) is a bioactive phospholipid that mediates a variety of biological actions through binding to G protein-coupled receptors known as LPA receptors (LPARs). In mammals, six LPAR subtypes (LPAR1-6) have been identified. This study aimed to determine the expression of LPAR4 in the developing mouse brain. Methods: Brains samples were prepared from mice in various stages of development and biochemical and immunohistochemical analyses were conducted using anti-LPAR4. Results: Western blot analysis detected two LPAR4-immunoreactive species at ∼50 kDa and ∼42 kDa from embryonic day 16.5 (E16.5). The ∼50 kDa molecule increased during development, reaching a peak at postnatal day 3 (P3), and then gradually decreased through P22. In contrast, the ∼42 kDa molecule continued to increase up to P22. Immunohistochemical analyses demonstrated strong LPAR4 expression in neural cells in the intermediate zone and cortical plate of the E15.5 cerebral cortex, whereas neural progenitors in the ventricular and subventricular zones exhibited weaker expression. At P15, fiber-like staining resembling the apical dendrites of cortical neurons and hippocampal pyramidal cells was also observed. Conclusion: This study demonstrated dynamic, spatiotemporal changes of LPAR4 expression in the brain from embryonic to postnatal stages. These findings support a potential role for LPAR4 in neural development.

Introduction: The combination of prenatal alcohol exposure (PAE) and placental insufficiency (PI) places infants at an increased risk for preterm birth and may worsen brain injury and neurobehavioral outcomes. In this preclinical study, the effect of PAE + PI on lateral, medial, and ventral prefrontal cortex (PFC), striatum and corpus callosum microstructure were investigated using diffusion tensor imaging (DTI). These brain regions are important for executive and higher cognitive functions, like cognitive flexibility. Methods: Pregnant Long-Evans rat dams voluntarily drank 5% ethanol in saccharin water or plain saccharin water until embryonic day 18 (E18) to mimic moderate PAE. On E19, an open laparotomy was completed, and the uterine arteries were transiently occluded for 1 h. The dams in the sham group underwent the same procedure, but without uterine artery occlusion. Offspring are delivered normally on E22 and matured with their dams. On postnatal day 35 (P35), tissue was collected from male and female rat offspring from all four prenatal treatment groups (Sham, PAE, PI, and PAE+PI). Fixed brain tissue was then scanned ex vivo on a Bruker 11.7 T magnetic resonance imaging. Fractional anisotropy (FA) and directional diffusion were measured in regions of interest. Two-way analysis of variance with Tukey’s correction was used, with p < 0.05 significant. Results: DTI analyses of the medial PFC (n = 14–30/group) revealed a significant impact of the prenatal exposure/insult on the FA (p < 0.05), with sham having the lowest FA (0.24 ± 0.01) and PI having the highest FA (0.28 ± 0.02) as well as a lower mean diffusivity (MD; 3.32 × 10−4 ± 2.35 × 10−5 mm2/s; p < 0.01) compared to PAE (4.35 × 10−4 ± 1.47 × 10−5 mm2/s). The lateral PFC was significantly impacted by prenatal exposure/insult with sham having the highest radial diffusivity (RD; 4.97 × 10−4 ± 2.20 × 10−5 mm2/s; p < 0.05) and MD (4.41 × 10−4 ± 2.10 × 10−5 mm2/s; p < 0.05) compared to the other groups. The striatum was sensitive to the prenatal exposure/insult, with the axial diffusivity (AD), RD, and MD all significantly increased in the PAE group and decreased in the PI group (p < 0.05). In the corpus callosum, the prenatal exposure/insult significantly decreased the AD (p < 0.05; PAE+PI AD: 5.00 × 10−4 ± 4.60 × 10−5 mm2/s). Conclusion: While all areas analyzed were impacted by the prenatal insults, the striatum, which consists primarily of efferent pathways, appears more vulnerable to injury compared to the PFC. Additional studies are needed to characterize the impact this may have on function related to these critical brain regions.

Introduction: Innervation of the paraventricular nucleus of the hypothalamus (PVN) by the orexigenic agouti-related protein (AgRP) and anorexigenic α-melanocyte-stimulating hormone (α-MSH) neurons of the arcuate nucleus (ARC) is a key element in the appetite-regulating neuronal circuitry whose development is influenced by circulating metabolic signals. In the present work, we studied if PVN innervation by the AgRP and α-MSH fibers is influenced by gut microbiota. Methods: To this aim, we compared, using immunohistochemistry, the innervation of PVN by AgRP and α-MSH fibers between germ-free and specific pathogen-free 7-week-old female mice. Results: We found that germ-free mice display an increased innervation of the PVN by both AgRP and α-MSH fibers, but also that the increase in AgRP fiber density was about twice as pronounced as that of α-MSH. Conclusion: These data reveal that gut microbiota plays a modulatory role in the development of the ARC/PVN axonal projections. An imbalance between AgRP and α-MSH innervation in germ-free mice may contribute to their metabolic and behavioral alterations.

Background: Small for gestational age (SGA) infants face a heightened risk of motor delays that can persist into childhood, affecting cognitive and language development. Early identification and intervention are critical for better long-term outcomes. Summary: This narrative review highlights evidence on motor development in SGA children, focusing on risk factors, neurobiological mechanisms, and early interventions. Motor delays in SGA infants correlate with lower birth weight, shorter gestation, adverse intrauterine conditions, and perinatal complications. Structural brain changes, especially in white matter and cerebellum, along with prenatal and postnatal inflammation, contribute to these deficits. Nutritional support, physical therapy, and family-based stimulation initiated in the first 2 years show promise for improving motor outcomes. Key Messages: SGA children are at high risk for motor developmental disorders. A comprehensive early intervention approach targeting nutrition, neurodevelopment, and family support is essential. Future research should aim to clarify mechanisms and optimize intervention timing and strategies to enhance long-term outcomes.

Introduction: Neurodevelopmental disorders (NDDs) are chronic conditions marked by abnormal brain development, presenting with significant clinical heterogeneity. Early diagnosis is crucial but challenging due to the complex symptoms. Genetic factors play a dominant role in NDD etiology. This study was to evaluate the diagnostic utility of dual-dimension whole-exome sequencing (WES) analysis in Chinese patients with NDDs and to deepen the understanding of genotype-phenotype correlations. Methods: This study retrospectively analyzed WES data of 128 Chinese NDD patients from Hubei Maternal and Child Health Hospital (July 2020–March 2024) for single-nucleotide variants (SNVs)/small insertions-deletions (Indels) and copy number variants (CNVs). Pathway enrichment, tissue-expression analyses, and functional experiments were conducted to interpret pathogenic genes and variants of uncertain significance. Results: The overall diagnostic rate for NDDs was 35.9% (46/128), with 28 cases confirmed by SNV/Indel analysis (30 variants in 29 genes) and 18 by CNV analysis (22 variants). Dual-dimension analysis markedly improved the diagnostic rate compared to conventional SNV/Indel analysis (35.9% vs. 21.9%). Patients with multisystem abnormalities had a higher diagnostic rate (63.2% vs. 31.2%). Among the 30 SNV/Indel variants, 86.7% (26) were de novo, and 70.0% (21) were novel. Recurrent pathogenic variants in ASXL3, SHANK3, and EHMT1 genes were identified. Most pathogenic genes were enriched in transcription-regulation pathways and highly expressed in the cerebellum and cerebral cortex. Functional experiments showed that the NLGN3 c.562G>A (p.G188R) hemizygous variant affects protein stability and is deleterious, aiding prenatal diagnosis and the birth of a healthy offspring. Conclusion: Integrating CNV analysis into routine WES workflows effectively clarifies the genetic heterogeneity of NDDs, expands the gene variant spectrum, and provides a basis for NDD prognosis assessment and precision diagnosis and treatment.