Frontiers in Molecular Neuroscience最新文献

Alpha-neurexins (α-Nrxns) are synaptic adhesion molecules that play crucial roles in synapse organization, specificity, and function. This review provides a comprehensive overview of α-Nrxns, covering their gene organization, molecular architecture, and roles in both physiological and pathological contexts. We begin by detailing the unique structural properties of α-Nrxns, particularly their large extracellular regions and complex alternative splicing, which facilitate diverse trans-synaptic interactions. We then examine their critical roles in regulating presynaptic neurotransmitter release, postsynaptic receptor function, and overall synaptic organization. While deletion of α-Nrxns in mice results in only modest morphological brain abnormalities, it causes profound deficits in synaptic function, underscoring their role in fine-tuning neural circuit activity in a context-dependent manner. We also explore how specific α-Nrxn ligands such as neurexophilins or IgSF21 contribute to synaptic diversity. Furthermore, we discuss emerging evidence linking α-NRXNs to various neurodevelopmental and psychiatric disorders, including autism spectrum disorder, schizophrenia, and intellectual disability. These links are supported by both genetic association studies and behavioral analyses in α-Nrxn mutant mice, which exhibit phenotypes that partially mirror symptoms observed in human disorders. Finally, we highlight recent advances in human induced pluripotent stem cell (hiPSC)-derived neuronal models, which offer powerful platforms to investigate α-NRXN-associated disease mechanisms at the cellular level. These models enable the study of patient-specific neurobiological alterations and support the development of targeted therapeutic strategies. Collectively, this review emphasizes the pivotal role of α-Nrxns in maintaining synaptic integrity and demonstrates how their dysfunction contributes to a broad spectrum of brain disorders, providing valuable insights for future translational research.

Habituation is evolutionary conserved and often considered as one of the simplest forms of learning, however, the underlying mechanisms are highly complex. Extensive research has been conducted over the last few decades to understand the mechanisms of habituation in vertebrate and invertebrate species. Zebrafish (Danio rerio) has emerged as a crucial model for exploring the underlying mechanisms of habituation. Due to the possibility for genetic manipulations and non-invasive visualization of neuronal activity across the entire larval brain and genetically encoded fluorescent sensors allowing the detection of different neurotransmitters linked to behavioral processes, larval zebrafish provides a great vertebrate model to investigate habituation learning. In our review, we summarize recent insights into habituation learning as well as habituation deficits under neuropathological conditions gained from zebrafish larvae.

Introduction: Metabolic syndrome (MetS) and Parkinson's disease (PD) share common pathophysiological and molecular impairments related to high PD incidence in MetS patients. In this study, we searched for independently MetS-associated single-nucleotide polymorphism variants (SNVs) in PD patients and aimed to explain the molecular mechanism involved.

Methods: We included 423 PD patients diagnosed by positron emission tomography (PET). A logistic regression model, the chi-squared analysis, and Fisher's exact test were applied to additive, dominant, and recessive genetic models of data obtained from the Parkinson's Progression Marker Initiative (PPMI) database. MicroRNA Quantitative trait Loci (MirQTL) analysis and microRNA binding to 5'/3'- untranslated regions (UTR) and conding sequence (CDS) region gene prediction analysis were performed. Expression quantitative trait loci mapping (eQTL) and gene prioritization using weighted co-expression network analysis were used to evaluate the molecular mechanisms. Chromosomal loci that explain variance in expression traits are referred to as eQTLs.

Results: The SNV variant rs1803274 was associated with MetS, increased cardiovascular risk, and altered butyrylcholinesterase levels. Eleven microRNAs binding to the BuChe 3'/'5-UTR and CDS region downregulated its expression. The rs1803274 variant was significantly enriched for neurotransmitter clearance, ghrelin secretion and deacylation, phosphatidylcholine synthesis, glycerophospholipid and lipid metabolism, and synaptic transmission. Forty-six eQTL proteins were associated with the SNV rs1803274. Thirteen of these were prioritized as potential therapeutic targets in a principal component analysis based on node degree parameters, betweenness centrality, and closeness centrality.

Conclusion and interpretation: The SNV variant rs1803274 was associated with both MetS and PD and downregulated the expression of BuChe, which is involved in ghrelin hydrolysis. This variant was associated with several MetS-related eQTLs proteins or their components.

It is estimated that 5%-40% of patients with pathological features of Alzheimer's disease (AD) maintain normal cognitive health throughout their lifetimes, a phenomenon known as cognitive resilience. Studies have identified many factors that contribute to a patient's capacity for resilience, with those that modulate gene expression being the most dynamic, adaptable, and potentially addressable as targets for future drug development. In patients cognitively resilient to AD and AD-related dementias (ADRD), transcriptional changes within specific cell types serve to preserve the processes most critical to cognitive function within each cell, exerting protective effects on other cell types as well via non-cell autonomous effects. Key themes in preserved cognitive function include maintenance of synaptic stability and function, dampening neuronal hyperexcitability, reducing misfolded protein accumulation, increasing myelination, and countering neuroinflammation. With future research on the most upstream and impactful transcriptional drivers, there lies immense potential for both therapeutics to address AD and a greater fundamental understanding of AD and the brain.

Zellweger spectrum disorders (ZSDs) are rare autosomal recessive conditions belonging to the larger group of peroxisome biogenesis disorders. The most prevalent form of ZSD is caused by mutations in the PEX1 gene, which encodes an AAA ATPase protein. Cells lacking functional PEX1 fail to import proteins crucial for the formation of competent peroxisomes, resulting in aberrant structures called ghost peroxisomes. Peroxisome dysfunction leads to the accumulation of compounds that are normally metabolized in this compartment, including very long-chain fatty acids (VLCFAs), pristanic and phytanic acids, as well as deficiency in compounds that are normally formed in this organelle, including docosahexaenoic acid (DHA) and plasmalogen precursors. Patients with a complete lack of PEX1 function develop severe symptoms and have a poor prognosis, with death in the first year of life. In the absence of effective treatments for ZSD, advancing our understanding of this complex multisystem disorder remains essential for uncovering new therapeutic opportunities. To this end, we generated and characterized a zebrafish model with Pex1 loss-of-function. Surprisingly, despite the early onset of disease-relevant features, about 10% of pex1 ^-/- zebrafish reached adulthood. However, this resilience was short-lived, as none of the mutant fish survived beyond one year. Histopathological analysis of the liver in adult pex1 ^-/- mutants revealed a profound peroxisomal import deficiency and severe vacuolation. Moreover, key metabolic hallmarks of ZSDs, including accumulation of VLCFAs and methyl-branched fatty acids phytanic and pristanic acid, were consistently detected in larval and adult pex1 ^-/- mutants. Transcriptomics analysis in pex1 ^-/- larvae revealed upregulation of ER-stress responses and pexophagy, as well as dysregulation of neurophysiological processes and visual perception. The latter findings were corroborated by abnormal locomotor behavior in the larvae and by disrupted outer nuclear and retinal layer architecture in adult mutant animals. The described zebrafish pex1 model provides a versatile in vivo platform to uncover novel disease-relevant pathways in ZSD and to investigate the physiological impact of VLCFAs and methyl-branched fatty acids. Its relative tolerance to Pex1 loss-of-function circumvents the early lethality observed in mouse models, enabling the study of ZSD pathophysiology beyond early developmental stages and offering a valuable tool for preclinical therapeutic exploration.

Drebrin (DBN), an actin-binding protein critical for the structural integrity and function of dendritic spines, is highly phosphorylated at steady state in neurons. Here, we investigate the phosphorylation dynamics of DBN in the context of chemically induced long-term depression (cLTD), a synaptic plasticity model mimicking activity-dependent weakening of synapses. Using biochemical analyses and mass spectrometry analyses, we show that DBN undergoes rapid and robust changes in phosphorylation following cLTD induction. Notably, cLTD triggers a marked decrease in many DBN phosphorylation sites, accompanied by proteolytic cleavage of the protein, suggesting a tightly regulated mechanism linking post-translational modification to structural remodelling of the synapse. Our findings highlight the dynamic regulation of DBN by phosphorylation during synaptic depression and support its potential role as a modulator of activity-dependent synaptic plasticity.

Introduction: Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either the TSC1 or TSC2 genes. These mutations prevent the TSC1/TSC2 protein complex from forming, resulting in hyperactivation of the mechanistic target of rapamycin (mTOR) cell growth and protein synthesis pathway. Epilepsy is one of the most common neurological symptoms in TSC patients, often associated with focal cortical lesions. However, it is not fully established whether such focal abnormalities are sufficient on their own to generate seizures and associated behavioral deficits. Here, we created a novel mouse model to test the hypothesis that a focal, postnatal deletion of Tsc2 from cortical neurons is sufficient to induce an epileptogenic network and produce behavioral changes relevant to TSC.

Methods: Tsc2 was deleted from neurons in a focal area of the frontal cortex in Tsc2 ^fl/fl (fTSC2 KO) mice following neonatal bilateral AAV9-CaMKII-Cre-mCherry injections on postnatal day 2. One group of adult fTSC2 KO and Tsc2 ^wt/wt (control) mice was implanted with cortical electrodes for combined video-EEG monitoring. A separate group of control and fTSC2 KO mice, injected with a lower viral titer, underwent video recording and behavioral exploration analysis in a novel environment. Tissue was collected for histology.

Results: All adult fTSC2 KO mice implanted with cortical electrodes had seizures, whereas no control mice did. Histological analyses showed that virally infected cells in fTSC2 KO mice had enlarged somas and increased mTOR activation (pS6 expression). These fTSC2 KO mice also had decreased parvalbumin and somatostatin interneuron densities in the surrounding cortex. fTSC2 KO mice displayed increased anxiety-like behaviors, spending significantly less time in the center of the novel environment compared to controls.

Conclusion: A focal, postnatal deletion of Tsc2 from cortical neurons is sufficient to cause both epilepsy and behavioral deficits in mice. This model recapitulates key phenotypes of TSC, including abnormal cell growth, reduced inhibitory cell density, and increased microglia activation. This fTSC2 KO model is advantageous for delineating the cortical changes that support epilepsy and behavioral deficits in TSC, and for investigating possible targets for therapeutic intervention.

Mutations in Fused in Sarcoma (FUS) are associated with neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This systematic review examined the connections between DNA damage in the central nervous system (CNS), dysfunction of DNA repair processes and the FUS proteinopathy. Twelve peer-reviewed publications were analyzed, investigating this question across a range of models, including immortalized cell lines, ALS-FTD patient-derived induced pluripotent stem cells, mouse tissues and post-mortem samples from ALS-FTD patients. The studies also explored the impact of inducing DNA damage using several agents, including calicheamicin and etoposide, on FUS pathology. Our findings indicated that accumulated DNA damage was documented in all twelve studies, with a key finding being the disruption of interactions between FUS and the DNA damage response (DDR). FUS interactions with various DDR and DNA repair proteins involved in sensing DNA damage and executing the major repair pathways were impaired, resulting in elevated levels of DNA damage in both the nucleus and mitochondria. Therefore, FUS is an essential protein for the preservation of genomic integrity and this loss of genome stability is likely to be a key contributor to the neurodegeneration in ALS-FTD.

Peripheral neuropathic pain is a chronic, secondary pain state caused by damage or diseases of the peripheral nervous system, typically accompanied by edema, inflammatory responses, increased neuronal excitability, and glutamate accumulation. Matrix metalloproteinase-9 (MMP-9), an important enzyme, plays a key role in various physiological and pathological processes, primarily by degrading the extracellular matrix. Recent studies have shown that MMP-9 plays a crucial role in the onset and progression of central nervous system disorders, particularly neuropathic pain. This review discusses the mechanisms underlying the involvement of MMP-9 in various models of peripheral neuropathic pain, with the aim of exploring its potential as a therapeutic target.