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Homocysteine (Hcy), a sulfur-containing amino acid derived from methionine, has been shown to be a significant and modifiable risk factor for various neurological disorders, including stroke, Parkinson’s disease, Alzheimer’s disease, and elderly depression. However, there is currently a lack of comprehensive understanding regarding the molecular mechanisms underlying Hcy-induced neurotoxicity. Therefore, this study aimed to establish rat and cell models of Hcy intervention in order to elucidate the underlying mechanism of neurotoxicity. Our research findings demonstrate that Hcy induces depressive - like symptoms in normal Sprague-Dawley rats. Pathological damage and apoptosis were detected in the DG, CA3, and CA1 regions of the hippocampus, along with the cortical area. Moreover, synaptic structural impairment was observed within the hippocampal. Simultaneously, Hcy promotes neuronal apoptosis and LDH leakage in mouse neuroblastoma (N2a) cells. Furthermore, we conducted mRNA microarray analysis to investigate differences in mRNA expressions and utilized Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis for gene function annotations in Hcy-treated N2a cells. The results highlighted significant alterations in 457 mRNAs in the Hcy-treated group compared to the Control group. Among the differentially expressed genes (DEGs), a total of 155 were found to be significantly up-regulated, while the remaining 302 were down-regulated. Furthermore, it was observed that four genes ( snap25 , cplx1 , slc32a1 and atp6v1e2 ) related to the synaptic vesicle cycle exhibited decreased expression in Hcy-treated N2a cells compared to the Control group. The expression levels of these four genes, as well as their corresponding proteins, were subsequently confirmed using RT-qPCR and western blot analysis, respectively. In conclusion, this study shed light on the detrimental impact of hyperhomocysteinemia on the nervous system, particularly with regard to the synaptic vesicle cycle.

Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active-zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through the interaction of VGLUT1 second proline-rich domain, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between Src homology three and proline-rich domains of synaptic proteins. In mammals, VGLUT1 gained a proline-rich sequence that recruits endophilinA1 and turns the transporter into a regulator of SV organization and spontaneous release.

Pituitary adenomas constitute 10 to 25% of intracranial tumors, rendering them one of the most prevalent types of brain tumors. While the majority of pituitary adenomas are benign, 35% exhibit invasive behavior. Compared with their non-invasive counterparts, invasive pituitary adenomas are more challenging to manage, highlighting the need to elucidate their underlying pathogenesis. However, the molecular mechanisms driving the invasive behavior of these tumors remain incompletely understood. Thus, the present study employed an integrated proteomic and metabolomic approach to investigate the molecular features associated with tumor invasiveness in pituitary adenomas. The investigation was performed at the First Affiliated Hospital of Xiamen University (Xiamen, China). Fresh-frozen tumor specimens were collected from 16 patients diagnosed with clinically non-functioning pituitary adenomas. These samples were divided into two groups based on invasiveness: Invasive tumors (n=8; Knosp grade ≥2) and non-invasive tumors (n=8; Knosp grade <2). Using data-independent acquisition mass spectrometry (MS) in conjunction with liquid chromatography-MS/MS metabolomics analysis, differentially expressed proteins (DEPs) and differentially expressed metabolites (DEMs) were identified. Comparative analysis identified 614 DEPs, including 286 proteins that were upregulated and 328 that were downregulated in invasive tumors relative to non-invasive tumors. Additionally, 74 DEMs were found, comprising 42 increased and 32 decreased metabolites. Enrichment analysis of pathways revealed notable involvement of the cyclic adenosine monophosphate (cAMP) signaling cascade, pathways related to pathogenic Escherichia coli (E. coli) infection and the synaptic vesicle cycle. Integration of the proteomic and metabolomic data underscored consistent changes within these biological pathways. The present investigation represents a comprehensive effort to combine proteomic and metabolomic approaches to characterize the invasive phenotype of pituitary adenomas. The identification of enriched pathways associated with cAMP signaling, E. coli infection and synaptic vesicle cycling provides new mechanistic understanding and offers potential biomarkers or therapeutic targets for differentiating tumor aggressiveness.

Exposure to heavy metal lead can cause serious health effects such as developmental neurotoxicity in infants, cognitive impairment in children, and cardiovascular and nephrotoxic effects in adults. Hearing loss is one of the toxic effects induced by exposure to lead. Previous studies demonstrated that exposure to lead causes oxidative stress in the cochlea and disrupts ribbon synapses in the inner hair cells. This study investigated the underlying mechanism by evaluating the changes in the abundance of cochlear synaptosomal proteins that accompany lead-induced cochlear synaptopathy and hearing loss in mice. Young-adult CBA/J mice were given lead acetate in drinking water for 28 days. Lead exposure significantly increased the hearing thresholds, particularly at the higher frequencies in both male and female mice, but it did not affect the activity of outer hair cells or induce hair cell loss. However, lead exposure decreased wave-I amplitude, suggesting lead-induced cochlear synaptopathy. In agreement, colocalization of pre- and post-synaptic markers indicated that lead exposure decreased the number of paired synapses in the basal turn of the cochlea. Proteomics analysis indicated that lead exposure increased the abundance of 352 synaptic proteins and decreased the abundance of 394 synaptic proteins in the cochlea. Bioinformatics analysis indicated that proteins that change in abundance are highly enriched in the synaptic vesicle cycle pathway. Together, these results suggest that outer hair cells are not the primary target in lead-induced ototoxicity, that lead-induced cochlear synaptopathy is more pronounced in the basal turn of the cochlea, and that synaptic vesicle cycle signaling potentially plays a critical role in lead-induced cochlear synaptopathy.

A present review is devoted to the analysis of literature data and results of own research. Skeletal muscle neuromuscular junction is specialized to trigger the striated muscle fiber contraction in response to motor neuron activity. The safety factor at the neuromuscular junction strongly depends on a variety of pre- and postsynaptic factors. The review focuses on the crucial role of membrane cholesterol to maintain a high efficiency of neuromuscular transmission. Cholesterol metabolism in the neuromuscular junction, its role in the synaptic vesicle cycle and neurotransmitter release, endplate electrogenesis, as well as contribution of cholesterol to the synaptogenesis, synaptic integrity, and motor disorders are discussed.

Sustained synaptic transmission requires the continuous replenishment of released synaptic vesicles (SVs). This process is particularly critical in neuronal circuits that operate at high rates and with high temporal precision, such as those in the auditory brainstem. Here, we investigated the effect of SV (re-)filling on inhibitory synapses between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO). These synapses transmit information with high speed and fidelity, properties essential for auditory computations such as sound localization. We specifically examined the role of the vacuolar ATPase (V-ATPase), a proton pump that acidifies the SV lumen to enable neurotransmitter loading. Using patch-clamp recordings in acute mouse slices, we assessed synaptic function under control conditions and during continuous V-ATPase inhibition with bafilomycin or folimycin. Contrary to our initial hypothesis, pharmacological inhibition caused only moderate impairment of sustained transmission. Even under high drug concentrations and intense stimulation (e.g., 100 Hz for 4 min), steady-state responses declined only to ~33% of control. Similar reductions were observed in the replenishment rate, the size of the readily releasable pool, and the cumulative eIPSC amplitude. Quantal size decreased gradually, reaching ~70% of control. Recovery from synaptic depression persisted in the presence of V-ATPase blockade, although it was less efficient. Together, these findings indicate that MNTB-LSO synapses are relatively resistant to V-ATPase inhibition, suggesting that SV replenishment does not rely solely on V-ATPase activity. Alternative acidification mechanisms may contribute, and among potential candidates, the Na + /H + exchanger isoform NHE6 showed strong immunoreactivity in glycinergic MNTB axon terminals contacting LSO somata. This identifies NHE6 as a promising target for future investigation.

Spinal cord injury (SCI) leads to motor and sensory impairment below the site of injury, thereby necessitating rehabilitation. An enriched environment (EE) increases social interaction and locomotor activity in a mouse model, similar to human rehabilitation. However, the impact of EE on presynaptic plasticity in gene expression levels remains unclear. Hence, this study aimed to investigate the therapeutic potential of EE in an SCI mouse model. Mice with spinal cord contusion were divided into two groups: those housed in standard cages (control) and those in EE conditions (EE). Each group was housed separately for either 2- or 8-weeks post-injury, after which RNA sequencing was performed and compared to a sham group (receiving only a dorsal laminectomy). The synaptic vesicle cycle (SVC) pathway and related genes showed significant downregulation after SCI at both time points. Subsequently, we investigated whether exposure to EE for 2- and 8-weeks post-SCI could modulate the SVC pathway and its related genes. Notably, exposure to EE for 8 weeks resulted in a marked reversal effect of SVC-related gene expression, along with stimulation of axon regeneration and mitigation of locomotor activity loss. Thus, prolonged exposure to EE increased presynaptic activity, fostering axon regeneration and functional improvement by modulating the SVC in the SCI mouse model. These findings suggest that EE exposure proves effective in inducing activity-dependent plasticity, offering a promising therapeutic approach akin to rehabilitation training in patients with SCI.

Beside its widely studied role in the pathogenesis of Alzheimer's disease (AD), β-amyloid (Aβ) is a normal and soluble product of neuronal metabolism that regulates several key physiological functions, exerting neuromodulatory effects on synaptic plasticity, memory, and neurotransmitter release. Such effects have been observed to occur in a hormetic fashion, with Aβ exhibiting a dual role influenced by its concentration, the different isoforms, or aggregation forms of the peptide. However, to date, our knowledge about the physiological functions of Aβ and, in particular, its modulatory role on synaptic activity and neurotransmission in the normal brain is fragmentary, thus hindering a clear comprehension of the biological mechanisms underlying the derangement from function to dysfunction. In particular, according to the amyloid cascade hypothesis, the switch from physiology to pathology is linked to the abnormal increase in Aβ levels, due to an imbalance in Aβ production and clearance. In this regard, increased Aβ levels have been hypothesized to induce early defects in synaptic function and such alterations have been suggested to account, at least in part, for the onset of neuropsychiatric symptoms (e.g., apathy, anxiety, changes in mood, depression, and agitation/aggression), frequently observed in the prodromal stage of AD. Therefore, understanding the biological mechanisms underlying early synaptic alterations in AD is a key starting point to frame the relevant time windows for AD treatment and to gain insight into AD etiopathogenesis.

Lithium is a mood stabilizer broadly used to prevent and treat symptoms of mania and depression in people with bipolar disorder (BD). Little is known, however, about its mode of action. Here, we analyzed the impact of lithium on synaptic vesicle (SV) cycling at presynaptic terminals releasing glutamate, a neurotransmitter previously implicated in BD and other neuropsychiatric conditions. We used the pHluorin-based synaptic tracer vGpH and a fully automated image processing pipeline to quantify the effect of lithium on both SV exocytosis and endocytosis in hippocampal neurons. We found that lithium selectively reduces SV exocytic rates during electrical stimulation, and markedly slows down SV recycling post-stimulation. Analysis of single-bouton responses revealed the existence of functionally distinct excitatory synapses with varying sensitivity to lithium—some terminals show responses similar to untreated cells, while others are markedly impaired in their ability to recycle SVs. While the cause of this heterogeneity is unclear, these data indicate that lithium interacts with the SV machinery and influences glutamate release in a large fraction of excitatory synapses. Together, our findings show that lithium down modulates SV cycling, an effect consistent with clinical reports indicating hyperactivation of glutamate neurotransmission in BD.

Understanding the genetic architecture of metabolic epilepsies is of paramount importance, both to current clinical practice and for the identification of further research directions. The main goals of our study were to identify the scope of metabolic epilepsies and to investigate their clinical presentation, diagnostic approaches and treatments. The International Classification of Inherited Metabolic Disorders and IEMbase were used as a basis for the identification and classification of metabolic epilepsies. Six hundred metabolic epilepsies have been identified, accounting for as much as 37% of all currently described inherited metabolic diseases (IMD). Epilepsy is a particularly common symptom in disorders of energy metabolism, congenital disorders of glycosylation, neurotransmitter disorders, disorders of the synaptic vesicle cycle and some other IMDs. Seizures in metabolic epilepsies may present variably, and most of these disorders are complex and multisystem. Abnormalities in routine laboratory tests and/or metabolic testing may be identified in 70% of all metabolic epilepsies, but in many cases they are non-specific. In total, 111 metabolic epilepsies (18% of all) have specific treatments that may significantly change health outcomes if diagnosed in time. Although metabolic epilepsies comprise an important and significant group of disorders, their real scope and frequency may have been underestimated.