Exposure to fine particulate matter (PM2.5) is implicated in neurodevelopmental disorders including cognitive decline, attention-deficit/hyperactivity disorder, and autism spectrum disorder. However, the specific molecular mechanisms by which PM2.5 impacts neurodevelopment are poorly understood. Accordingly, in the present study, the role of protein kinase A (PKA)/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling in PM2.5-induced neurodevelopmental damage was investigated using primary cultured hippocampal neurons. When hippocampal neurons cultured for 3 days in vitro (DIV3) were exposed to PM2.5 for 24 h and 96 h, neuronal viability decreased by 18.8% and 32.7% respectively, percentage of TUNEL-positive neurons increased by 78.5% and 64.0% separately, caspase-9 expression increased, lower postsynaptic density and shorter active zones were observed by transmission electron microscopy, expression of synapse-related proteins including postsynaptic density-95 (PSD95), growth associated protein-43 (GAP43), and synaptophysin (SYP) were decreased, and the phosphorylation levels of PKA, CREB, and BDNF expression also decreased. However, the PM2.5-induced neuronal damage could be ameliorated or aggravated to varying degrees by up- or down-regulation of the PKA/CREB/BDNF signaling pathway, respectively. Our results indicate that PM2.5 exposure exerts neurodevelopmental toxicity as indicated by lower viability, apoptosis, and synaptic damage in primary cultured hippocampal neurons, and that the PKA/CREB/BDNF pathways could play a vital role in PM2.5-mediated neurodevelopmental toxicity.

Background: Migraine is a common neurological disorder with a strong genetic component. Despite the identification of over 100 loci associated with migraine susceptibility through genome-wide association studies (GWAS), the underlying causative genes and biological mechanisms remain predominantly elusive. Methods: The FinnGen R10 dataset, consisting of 333,711 subjects (20,908 cases and 312,803 controls), was utilized in conjunction with the Genotype-Tissue Expression Project (GTEx) v8 EQTls files to conduct cross-tissue transcriptome association studies (TWAS). Functional Summary-based Imputation (FUSION) was employed to validate these findings in single tissues. Additionally, candidate susceptibility genes were screened using Gene Analysis combined with Multi-marker Analysis of Genomic Annotation (MAGMA). Subsequent Mendelian randomization (MR) and colocalization analyses were conducted. Furthermore, GeneMANIA analysis was employed to enhance our understanding of the functional implications of these susceptibility genes. Results: We identified a total of 19 susceptibility genes associated with migraine in the cross-tissue TWAS analysis. Two novel susceptibility genes, REV1 and SREBF2, were validated through both single tissue TWAS and MAGMA analysis. Mendelian randomization and colocalization analyses further confirmed these findings. REV1 may reduce the migraine risk by regulating DNA damage repair, while SREBF2 may increase the risk of migraine by regulating cholesterol metabolism. Conclusion: Our study identified two novel genes whose predicted expression was associated with the risk of migraine, providing new insights into the genetic framework of migraine.