Autism spectrum disorder (ASD) exhibits substantial heterogeneity, wherein genetic and idiopathic forms may converge on shared core phenotypes through divergent molecular pathways. The histone variant macroH2A1.1, implicated in chromatin repression and DNA repair, has been linked to behavioral alterations opposite to core ASD features when depleted systemically. However, its regional and cell-type-specific regulation in genetic versus idiopathic ASD models remains unclear. We investigated macroH2A1.1 expression across the dorsal striatum, hippocampus, and medial prefrontal cortex in Fmr1 knockout (Fragile X syndrome model) and BTBR T+ Itpr3tf/J (idiopathic ASD model) mice. Quantitative PCR and imaging analyses revealed opposing patterns: BTBR mice showed region-specific mRNA downregulation and increased strongly stained macroH2A1.1-positive nuclei, whereas Fmr1 knockout mice exhibited reduced strong staining with increased weak staining, specific to neurons and not astrocytes, independent of significant mRNA changes. Bulk RNA-seq meta-analysis and pseudobulk single-cell transcriptomics further identified pathway-level enrichment of oxidative phosphorylation, chromatin remodeling, and transcriptional repression functional gene sets in unmatched public datasets (BTBR striatum; FXS hippocampus and cortex), with pronounced neuron-astrocyte divergence in Fmr1 knockout cortex. These findings underscore distinct epigenetic regulatory mechanisms in genetic and idiopathic ASD models.
The neutralization of interleukin-16 (IL-16) or of its main target, CD4 receptors, as well as the reduction of its synthesis by inhibiting caspase-3 have been recently considered as possible strategies to inhibit pain. Here we study the involvement of peripheral mechanisms related to the IL-16/CD4 axis in the nociceptive responses evoked after ligation of sciatic nerve in mice. Systemic administration of anti-IL-16 or anti-CD4 antibodies inhibited hyperalgesia and allodynia measured 2 days after ligation in male and female mice. In addition, both antibodies were also analgesic 9 days after nerve ligation, supporting the participation of IL-16 and CD4 in the establishment and maintenance of neuropathic pain. Following nerve injury, Il16 expression remained unaltered in dorsal root ganglia (DRGs) and damaged nerves, whereas Casp3 expression increased in DRGs and the enzymatic activity of caspase-3 was enhanced in damaged nerves. Immunofluorescence assays demonstrated a limited presence of IL-16 in DRG neurons, that remained unmodified after injury, and a clear up-regulation of this cytokine in injured nerves. Double immunofluorescence assays with βIII-tubulin and S100β antibodies demonstrated that IL-16 is expressed both in axons and Schwann cells after nerve ligation. The ability of IL-16 to evoke nociception by directly acting on nerves was confirmed by intra-sciatic administration. Immunofluorescence labelling of CD4 receptors was also present in injured nerves, being also up-regulated both in axons and Schwann cells. Finally, hyperalgesia and allodynia were prevented by the intra-sciatic administration of anti-IL-16 or anti-CD4 antibodies, thus supporting the relevance of the IL-16/CD4 axis in neuropathic hypernociception.
Persistent neuroinflammation is a central feature of brain aging and a common pathological context across neurodegenerative diseases. Although microglial activation has been extensively studied, why inflammatory responses in aging brains become increasingly difficult to resolve remains insufficiently understood. In this review, we propose inflammometabolic locking as an evidence-informed working framework describing impaired recovery and declining reversibility of microglial states. Rather than viewing persistent neuroinflammation simply as prolonged activation, the framework emphasizes failure of inflammatory exit and homeostatic re-entry. We integrate current evidence across four interrelated domains: metabolic remodeling, defective lipid handling and post-phagocytic processing, disrupted organelle homeostasis, and persistent transcriptional and epigenetic remodeling. Abnormalities across these domains may become functionally coupled and mutually reinforcing, progressively limiting microglial plasticity and recovery. Their pathological significance therefore depends not only on their presence, but also on whether they resolve as pathological burden declines and whether clearance, repair, and homeostatic functions recover. By distinguishing transient adaptation from locking-like states, this recovery-oriented framework suggests that therapeutic strategies should aim not only to suppress inflammatory output but also to restore microglial recovery capacity. Inflammometabolic locking remains a working hypothesis requiring longitudinal and intervention-based validation.
To identify mitochondrial genes associated with trigeminal neuralgia (TN) and characterize their expression in patient blood and experimental trigeminal nerve injury. We integrated methylation, expression, and protein quantitative trait loci with FinnGen TN genome-wide association data, focusing on MitoCarta3.0 genes. Summary-data-based Mendelian randomization, heterogeneity testing, colocalization, and tissue-specific analyses prioritized candidates. An exploratory case–control expression analysis measured candidate-gene expression by reverse-transcription quantitative polymerase chain reaction in pretreatment blood from 12 patients with TN and 12 controls; experimental analyses examined blood and selected tissues from six rats with infraorbital nerve chronic constriction injury (ION-CCI) and six sham-operated rats. Longitudinal behavioral testing characterized the injury model. NIT2, HDHD3, and GRHPR overlapped across the three molecular screens. Colocalization supported NIT2 in the anterior cingulate cortex (PP.H4 = 0.949) and GRHPR in tibial nerve (PP.H4 = 0.818). All three genes showed increased expression in patient blood (all false-discovery-rate q < 0.001). HDHD3 and GRHPR also increased in rat blood (both q = 0.0188), and GRHPR increased in the injured infraorbital nerve (q = 0.0076). Genetically predicted higher GRHPR expression was associated with lower TN risk. Human genetics and cross-species expression analyses identify mitochondrial candidates associated with TN and trigeminal nerve injury. The protective genetic direction and injury-associated expression of GRHPR support a hypothesis of compensatory metabolic adaptation in trigeminal pain.
