To present the expression of calsyntenin-1 (Clstn1) in the brain and investigate the potential mechanism of Clstn1 in lithium-pilocarpine rat seizure models. Thirty-five male SD adult rats were induced to have seizures by intraperitoneal injection of lithium chloride pilocarpine. Rats exhibiting spontaneous seizures were divided into the epilepsy (EP) group (n = 15), whereas those without seizures were divided into the control group (n = 14). Evaluate the expression of Clstn1 in the temporal lobe of two groups using Western blotting, immunohistochemistry, and immunofluorescence. Additionally, 55 male SD rats were subjected to status epilepticus (SE) using the same induction method. Rats experiencing seizures exceeding Racine\'s level 4 (n = 48) were randomly divided into three groups: SE, SE + control lentivirus (lentiviral vector expressing green fluorescent protein [LV-GFP]), and SE + Clstn1-targeted RNA interference lentivirus (LV-Clstn1-RNAi). The LV-GFP group served as a control for the lentiviral vector, whereas the LV-Clstn1-RNAi group received a lentivirus designed to silence Clstn1 expression. These lentiviral treatments were administered via hippocampal stereotactic injection 2 days after SE induction. Seven days after SE, Western blot analysis was performed to evaluate the expression of Clstn1 in the hippocampus and temporal lobe. Meanwhile, we observed the latency of spontaneous seizures and the frequency of spontaneous seizures within 8 weeks among the three groups. The expression of Clstn1 in the cortex and hippocampus of the EP group was significantly increased compared to the control group (p < .05). Immunohistochemistry and immunofluorescence showed that Clstn1 was widely distributed in the cerebral cortex and hippocampus of rats, and colocalization analysis revealed that it was mainly co expressed with neurons in the cytoplasm. Compared with the SE group (11.80 ± 2.17 days) and the SE + GFP group (12.40 ± 1.67 days), there was a statistically significant difference (p < .05) in the latency period of spontaneous seizures (15.14 ± 2.41 days) in the SE + Clstn1 + RNAi group rats. Compared with the SE group (4.60 ± 1.67 times) and the SE + GFP group (4.80 ± 2.05 times), the SE + Clstn1 + RNAi group (2.0 ± .89 times) showed a significant reduction in the frequency of spontaneous seizures within 2 weeks of chronic phase in rats (p < .05). Elevated Clstn1 expression in EP group suggests its role in EP onset. Targeting Clstn1 may be a potential therapeutic approach for EP management.

Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks. Abnormal synaptogenesis plays a vital role in the formation of overexcited networks. Recent evidence has confirmed that thrombospondin-1 (TSP-1), mainly secreted by astrocytes, is a critical cytokine that regulates synaptogenesis during epileptogenesis. Furthermore, numerous studies have reported that TSP-1 is also involved in other processes, such as angiogenesis, neuroinflammation, and regulation of Ca2+ homeostasis, which are closely associated with the occurrence and development of epilepsy. In this review, we summarize the potential contributions of TSP-1 to epilepsy development.

Neonatal jaundice is one of the most common disorders in the first 2 wk after birth. Unconjugated bilirubin (UCB) is neurotoxic and can cause neurological dysfunction; however, the underlying mechanisms remain unclear. Neurogenesis, neuronal growth, and synaptogenesis are exuberant in the early postnatal stage. In this study, the impact of UCB on neuritogenesis and synaptogenesis in the early postnatal stage was evaluated both in vitro and in vivo. Primary culture neuronal stem and progenitor cells (NSPCs) were treated with UCB during differentiation, and then the neurite length and synapse puncta were measured. In the bilirubin encephalopathy (BE) animal model, DCX+-marked developing neurons were used to detect apical length and dendritic arborization. According to the data, UCB significantly reduced neurite length and synapse density, as well as decreased the apical dendrite length and dendritic arborization. Furthermore, the NMDAR subunit NR2B was downregulated in NSPCs, while pCREB expression in the hippocampus progressively decreased during disease progression in the BE model. Next, we tested the expression of NR2B, pCREB, mBDNF, and p-mTOR in NSPCs in vitro, and found that UCB treatment reduced the expression of these proteins. In summary, this suggests that UCB causes chronic neurological impairment and is related to the inhibition of NMDAR-CREB-BDNF signaling in NSPCs, which is associated with reduced neuritogenesis and synaptogenesis. This finding may inspire the development of novel pharmaceuticals and treatments.

The formation and maintenance of synapses are precisely regulated, and the misregulation often leads to neurodevelopmental or neurodegenerative disorders. Besides intrinsic genetically encoded signaling pathways, synaptic structure and function are also regulated by extrinsic factors, such as nutrients. O-GlcNAc transferase (OGT), a nutrient sensor, is abundant in the nervous system and required for synaptic plasticity, learning, and memory. However, whether OGT is involved in synaptic development and the mechanism underlying the process are largely unknown. In this study, we found that OGT-1, the OGT homolog in C. elegans, regulates the presynaptic assembly in AIY interneurons. The insulin receptor DAF-2 acts upstream of OGT-1 to promote the presynaptic assembly by positively regulating the expression of ogt-1. This insulin-OGT-1 axis functions most likely by regulating neuronal activity. In this study, we elucidated a novel mechanism for synaptic development, and provided a potential link between synaptic development and insulin-related neurological disorders.

BACKGROUND: In the ancient book \"Shen Nong\'s Herbal Classic,\" Panax ginseng CA Mey was believed to have multiple benefits, including calming nerves, improving cognitive function, and promoting longevity. Ginsenosides are the main active ingredients of ginseng. Ginsenoside RK3 (RK3), a rare ginsenoside extracted from ginseng, displays strong pharmacological potential. However, its effect on neurogenesis remains insufficiently investigated.
OBJECTIVE: This study aims to investigate whether RK3 improves learning and memory by promoting neurogenesis, and to explore the mechanism of RK3 action.
METHODS: The therapeutic effect of RK3 on learning and memory was determined by the Morris water maze (MWM) and novel object recognition test (NORT). The pathogenesis and protective effect of RK3 on primary neurons and animal models were detected by immunofluorescence and western blotting. Protein expression of cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway was detected by western blotting.
RESULTS: Our results showed that RK3 treatment significantly improved cognitive function in APPswe/PSEN1dE9 (APP/PS1) mice and C57BL/6 (C57) mice. RK3 promotes neurogenesis and synaptogenesis in the mouse hippocampus. In vitro, RK3 prevents Aβ-induced injury in primary cultured neurons and promotes the proliferation of PC12 as well as the expression of synapse-associated proteins. Mechanically, the positve role of RK3 on neurogenesis was combined with the activation of CREB/BDNF pathway. Inhibition of CREB/BDNF pathway attenuated the effect of RK3.
CONCLUSIONS: In conclusion, this study demonstrated that RK3 promotes learning and cognition in APP/PS1 and C57 mice by promoting neurogenesis and synaptogenesis through the CREB/BDNF signaling pathway. Therefore, RK3 is expected to be further developed into a potential drug candidate for the treatment of Alzheimer\'s disease (AD).

Alzheimer\'s disease (AD), recognized as the leading cause of dementia, occupies a prominent position on the list of significant neurodegenerative disorders, representing a significant global health concern with far-reaching implications at both individual and societal levels. The primary symptom of Alzheimer\'s disease is a decrease in synaptic potency along with synaptic connection loss. Synapses, which act as important linkages between neuronal units within the cerebral region, are critical in signal transduction processes essential to orchestrating cognitive tasks. Synaptic connections act as critical interconnections between neuronal cells inside the cerebral environment, facilitating critical signal transduction processes required for cognitive functions. The confluence of axonal and dendritic filopodial extensions culminates in the creation of intercellular connections, coordinated by various signals and molecular mechanisms. The progression of synaptic maturation and plasticity is a critical determinant in maintaining mental well-being, and abnormalities in these processes have been linked to the development of neurodegenerative diseases. Wnt signaling pathways are important to the orchestration of synapse development. This review examines the complicated interplay between Wnt signaling and dendritic filopodia, including an examination of the regulatory complexities and molecular machinations involved in synaptogenesis progression. Then, these findings are contextualized within the context of AD pathology, allowing for the consideration of prospective therapeutic approaches based on the findings and development of novel avenues for future scientific research.

Development is a complex process involving precise regulation. Developmental regulation may vary in tissues and individuals, and is often altered in disorders. Currently, the regulation of developmental timing across neocortical areas and developmental changes in Down syndrome (DS) brains remain unclear. The changes in regulation are often accompanied by changes in the gene expression trajectories, which can be divided into two scenarios: (1) changes of gene expression trajectory shape that reflect changes in cell type composition or altered molecular machinery; (2) temporal shift of gene expression trajectories that indicate different regulation of developmental timing. Therefore, we developed an R package TempShift to separates these two scenarios and demonstrated that TempShift can distinguish temporal shift from different shape (DiffShape) of expression trajectories, and can accurately estimate the time difference between multiple trajectories. We applied TempShift to identify sequential gene expression across 11 neocortical areas, which suggested sequential occurrence of synapse formation and axon guidance, as well as reconstructed interneuron migration pathways within neocortex. Comparison between healthy and DS brains revealed increased microglia, shortened neuronal migration process, and delayed synaptogenesis and myelination in DS. These applications also demonstrate the potential of TempShift in understanding gene expression temporal dynamics during different biological processes.

Ketamine is an ionic glutamic acid N-methyl-d-aspartate receptor (NMDAR) antagonist commonly used in clinical anesthesia, and its rapid and lasting antidepressant effect has stimulated great interest in psychology research. However, the molecular mechanisms underlying its antidepressant action are still undetermined. Sevoflurane exposure early in life might induce developmental neurotoxicity and mood disorders. In this study, we evaluated the effect of ketamine against sevoflurane-induced depressive-like behavior and the underlying molecular mechanisms. Here, we reported that A2AR protein expression was upregulated in rats with depression induced by sevoflurane inhalation, which was reversed by ketamine. Pharmacological experiments showed that A2AR agonists could reverse the antidepressant effect of ketamine, decrease extracellular signal-regulated kinase (ERK) phosphorylation, reduce synaptic plasticity, and induce depressive-like behavior. Our results suggest that ketamine mediates ERK1/2 phosphorylation by downregulating A2AR expression and that p-ERK1/2 increases the production of synaptic-associated proteins, enhancing synaptic plasticity in the hippocampus and thereby ameliorating the depressive-like behavior induced by sevoflurane inhalation in rats. This research provides a framework for reducing anesthesia-induced developmental neurotoxicity and developing new antidepressants.

It is a big challenge to design a biomimetic physical microenvironment with greater similarity to in vivo tissue to observe real cell behaviors. We established a novel cell culture platform based on patterned equidistant micropillars with stiff and soft stiffnesses to mimic the changes that happened in the transition from normal to osteoporotic disease. We first demonstrated that the soft micropillar substrate decreased osteocyte synaptogenesis through synaptogyrin 1 and that this decrease was accompanied by impairment of cell mechanoperception and a decrease in cellular cytoskeletal rearrangement. We then found that the soft equidistant micropillar substrate reduced the osteocyte synaptogenesis mainly via the inactivation of Erk/MAPK signaling. We finally found that soft micropillar substrate-mediated synaptogenesis impacted the cell-to-cell communication and matrix mineralization of osteocytes. Taken together, this study provides evidence of cellular mechanical responses that are much more similar to those of real osteocytes at the bone tissue level.

Alternative pre-mRNA splicing, which produces various mRNA isoforms with distinct structures and functions from a single gene, is regulated by specific RNA-binding proteins and is an essential method for regulating gene expression in mammals. Recent studies have shown that abnormal change during neuronal development triggered by splicing mis-regulation is an important feature of various neurological diseases. Polypyrimidine tract binding protein 1 (PTBP1) is a kind of RNA-binding proteins with extensive biological functions. As a well-known splicing regulator, it affects the neuronal development process through its involvement in axon formation, synaptogenesis, and neuronal apoptosis, according to the most recent studies. Here, we summarized the mechanism of alternative splicing, structure and function of PTBP1, and the latest research progress on the role of alternative splicing events regulated by PTBP1 in axon formation, synaptogenesis and neuronal apoptosis, to reveal the mechanism of PTBP1-regulated changes in neuronal development process.