Synapse最新文献

Brain plasticity enables adaptive learning, memory, and behavior, yet it is neither unconstrained nor automatic. Emerging evidence indicates that synaptic change occurs within a hierarchy of interacting regulatory layers that collectively determine when, where, and how plasticity is expressed. We propose a four-layer hierarchical framework in which plasticity is shaped by energetic constraints, homeostatic stability, neuromodulatory gating, and experience-dependent synaptic modification. Energetic limits set metabolic boundaries for synaptic change, while homeostatic mechanisms maintain network excitability and excitation-inhibition balance. Neuromodulators, including dopamine, acetylcholine, noradrenaline, and serotonin, dynamically gate plasticity based on behavioral relevance, salience, and internal state. Finally, Hebbian and spike-timing-dependent mechanisms implement input-specific synaptic modifications that encode adaptive information. Dysregulation at any of these layers is proposed to contribute to clinical deficits: insufficient gating impairs learning and motivation, excessive or shifted gating balance stabilizes maladaptive circuits or distorts salience, and reduced consistency in gating dynamics undermines attention and flexibility. This perspective reframes neurological and psychiatric disorders as conditions of controlled plasticity failure (i.e., failure of one or more regulatory layers to appropriately permit or restrict synaptic change) rather than simple neurotransmitter imbalances. By integrating metabolic, cellular, circuit, and behavioral dimensions, our framework provides a mechanistic understanding of adaptive and maladaptive plasticity, offering principles to guide therapeutic interventions that restore context-appropriate learning and cognitive function.

Epilepsy is a complex neurological disorder characterized by recurrent seizures resulting from an imbalance between excitatory and inhibitory neurotransmission. γ-Aminobutyric acid type A receptors (GABA_ARs), the principal mediators of fast inhibitory synaptic transmission, are essential for maintaining neuronal stability. Their function depends on tightly regulated trafficking processes, including subunit assembly in the endoplasmic reticulum, transport through the Golgi apparatus, membrane insertion, synaptic targeting, stabilization, and recycling. Disruptions in these processes, caused by genetic mutations, aberrant posttranslational modifications, or seizure-induced neuronal activity, impair receptor surface expression and localization, reducing inhibitory signaling and promoting network hyperexcitability. Evidence from human and animal studies indicates that altered GABA_AR trafficking contributes to epileptogenesis and pharmacoresistance, particularly during severe conditions such as status epilepticus. Understanding the molecular mechanisms regulating GABA_AR trafficking provides insights into epilepsy pathophysiology and highlights potential therapeutic strategies aimed at restoring inhibitory balance. By linking these trafficking mechanisms to synaptic structure and ion channel function, this review situates GABA_AR biogenesis within the broader framework of synaptic organization relevant to epilepsy and other neurological disorders.

Corticotropin-releasing factor receptor 1 (CRFR1) plays a role in stress-induced hippocampal plasticity that can affect learning and memory processes including those important for addiction. Our prior work revealed sex differences in the distribution of CRFR1 within CA3 pyramidal cells and hilar interneurons in rats that could differentially affect associative learning processes in females and males, especially in response to chronic immobilization stress (CIS). Here, we examine the effect of oxycodone (Oxy) conditioned place preference (CPP) in unstressed and CIS adult female and male rats on the subcellular distribution of CRFR1 in CA3 pyramidal cells and dentate gyrus (DG) hilar interneurons using immuno-electron microscopy. After Oxy CPP, males compared to females had greater plasmalemmal-associated CRFR1 in CA3 pyramidal cell and DG interneuron dendrites, consistent with a greater binding capacity for corticotropin-releasing factor (CRF) in males. CIS alone resulted in increases in corticotropin-releasing hormone receptor 1 (Crhr1) mRNA in the pyramidal cell layer and stratum oriens of CA3 in males. Following CIS and Oxy CPP behavior, only females acquired CPP. Oxy CIS females compared to Oxy CIS males had more total CRFR1 in DG interneuron dendrites. Moreover, CRFR1 trafficked from the cytoplasm toward the plasmalemma in DG interneuron dendrites in CIS Oxy females, indicating a potential greater binding capacity for CIS Oxy females in this neuronal population. These findings along with prior studies suggest that changes in CRFR1 and opioid receptor trafficking in CIS females contribute to mechanisms that are associated with the development of Oxy CPP in CIS females, but not males.

Background: Parkinson's disease (PD) is one of the common neurodegenerative diseases and is difficult to cure. The mechanisms underlying PD are incompletely understood.

Objective: This study investigated the changes in miR-650 expression in PD patients, aiming to assess its potential diagnostic value, and preliminarily explored the molecular mechanism by which miR-650 regulates oxidative damage and neuroinflammation.

Methods: The clinical data and blood samples were collected from PD patients. PD models were established in MPTP-treated mice and MPP+-treated BV2 cells. The function and molecular mechanism of miR-650 were then investigated through behavioral assessments, data analysis (such as ROC analysis and logistic regression analysis), and molecular analysis (such as Western blot, ELISA, and flow cytometry).

Results: miR-650 was upregulated in PD and exhibited diagnostic potential. The MPTP-induced PD mouse model displayed motor dysfunction, increased accumulation of α-synuclein, enhanced oxidative stress and inflammatory response. These symptoms were effectively alleviated by inhibiting miR-650. In BV2 cells, inhibiting miR-650 reduced oxidative stress and inflammatory responses by negatively regulating GCLM.

Conclusion: The upregulated expression of miR-650 may have potential diagnostic value in PD. Animal and cellular experiments indicate that inhibiting miR-650 alleviates the motor disorders, oxidative stress, and inflammatory responses in PD by negatively regulating GCLM.

This study aimed to investigate the role and underlying mechanism of lncRNA MIAT in sevoflurane (Sev)-induced cognitive dysfunction in neonatal rats, thereby offering theoretical basis for clinical intervention. Seven-day-old Sprague-Dawley (SD) rats were chosen to construct a Sev-induced cognitive dysfunction model. Anxiety-like behavior and locomotor activity were assessed by the open field test (OFT), whereas cognitive function was evaluated using novel object recognition (NOR) test and Morris water maze (MWM) test. The expression levels of lncRNA MIAT, miR-15b-5p, and Ccnd1 were detected by RT-qPCR. The dual-luciferase reporter gene assay was carried out to validate the targeted binding relationships. Sev exposure led to a downregulation of lncRNA MIAT expression in rat hippocampus. lncRNA MIAT alleviated Sev-induced cognitive impairment, as manifested by increased central zone residence time in OFT, elevated recognition index (RI) in NOR test, shortened escape latency, increased platform crossings, and prolonged target quadrant residence time in MWM test. Mechanistically, lncRNA MIAT directly targeted miR-15b-5p and inhibited its expression. miR-15b-5p targeted Ccnd1 and suppressed its expression. Overexpression of miR-15b-5p or silencing of Ccnd1 reversed the neuroprotective effect of lncRNA MIAT. LncRNA MIAT ameliorates Sev-induced cognitive dysfunction in neonatal rats by sponging miR-15b-5p to upregulate Ccnd1 expression, which may serve as a potential target for preventing Sev-related neurotoxicity.

Anorexia nervosa is a deadly eating disorder marked by extreme food restriction, compulsive exercise, and severe weight loss. In a prior study using the activity-based anorexia (ABA) animal model of anorexia nervosa, 30 mg/kg, but not 3 mg/kg, of ketamine reduced relapse vulnerability, measured as increased food intake, increased body weight (BW), and reduced excessive wheel running, though there were individual differences in responsiveness to treatment. This study investigated whether ketamine evoked sustained changes to AMPA receptors (AMPARs) at excitatory synapses of the prefrontal cortex (PFC), and whether they might correlate with individual differences in sustained behavioral improvements. Adolescent female mice that received 30 mg/kg (N = 8) or 3 mg/kg (N = 8) of ketamine underwent two cycles of ABA induction (ABA1 and ABA2), which included acclimation to a wheel preceding food restriction, with ABA2 modeling relapse. We analyzed the distributions of PFC AMPARs at synapses of pyramidal neurons (PNs) and of GABA interneurons (GABA-INs) using electron microscopy, with 10-nm immunogold to localize AMPARs. Increased AMPARs in the cytoplasm of PN synapses correlated with better BW retention during ABA2, as well as a reduction in excessive wheel running. Increased AMPARs in PN synapses' cytoplasm and GABA-INs synapses' postsynaptic density were associated with higher food intake during recovery. These correlations fit with a previous proposal that excitatory outflow from PFC to the GABA-INs in the dorsal raphe promotes feeding, while decreased excitatory outflow from PFC to dorsal medial striatum decreases hyperactivity during ABA, both of which contribute positively toward gain of resilience against ABA.

The cerebellin (CBLN) family includes CBLN1, CBLN2, CBLN3, and CBLN4, which are important secreted glycoproteins that play roles in synaptogenesis and the maintenance and plasticity of synapses across various regions of the central nervous system (CNS). Generally known for their implications in cerebellar parallel fiber-Purkinje cell synapses, CBLNs also play a comprehensive role in synaptic regulation in the CNS. By forming trans-synaptic complexes with postsynaptic glutamate delta receptors (GluDs) and presynaptic neurexins (NRXNs), CBLNs significantly impact the synaptic specificity and potency. Each CBLN protein has its own expression signature and function. Current research points to a key role for CBLN1 in forming excitatory synapses, especially in the cerebellum, while CBLN2 is reported to regulate inhibitory synaptic transmission and serotonergic circuits. In addition, CBLN3 regulates synaptic stability and is associated with many neurodevelopmental problems. Apart from its role in the regulation of inhibitory synapse formation, CBLN4 is also linked to many neurodegenerative disorders. Dysfunction of pathways associated with CBLN signaling has been linked to several neuropsychiatric and neurological disorders, such as ataxia and schizophrenia. This review article compares existing data on the structure, expression, and functional properties of CBLN proteins, their roles in synapse organization, and their potential as therapeutic targets for neurological disease.

In recent decades, the rate of aging has increased significantly worldwide. Since both cognitive and motor performance decline during aging, they are considered indicators of this stage of normal development. Successful, healthy aging-not associated with pathology-is accompanied by a decline in motor skills due to the underlying anatomical and functional organization of the motor cortex. Deep-layer V neurons are thought to be the relay that translates afferent information to this cortical region and the organizers of the output of information that generates motor activity. Basal dendritic arborization was studied using the Sholl method, along with dendritic spine density and the amounts of distinct spine types in medial segments of primary dendrites in deep pyramidal neurons of layer V of the motor cortex of young (3-4 months) and aged (22-24 months), male Sprague-Dawley rats. Significant reductions in dendritic arborization and spine density were observed in the aged animals. Each spine type-thin, mushroom, stubby, and wide-existed in lower numbers than in the young animals. Results suggest both a reduction in the integrative capacity of synaptic stimuli by pyramidal cells and a downregulation in the processing of excitatory information. These findings could underlie the decline in the acquisition and maintenance of motor skills during healthy aging.

The accumulation of tau tangles and Aβ plaques are prominent neuropathologies that characterize Alzheimer's disease (AD) and Down syndrome (DS). Continuous developments of PET tracers as biomarkers can be supported by autoradiography to validate effectiveness and accuracy of binding properties that elucidate the pathophysiology of DSAD and AD. This in vitro comparative study evaluates [¹²⁵I]IPPI binding to tau and [¹²⁵I]IBETA binding to Aβ plaques in the frontal cortex (FCX) and temporal cortex (TCX) of postmortem human brain slices of AD (n = 5), DSAD (n = 5), and cognitively normal (CN) (n = 5) cases. With anti-tau and anti-Aβ immunostains confirming the presence of tau and Aβ plaques, [¹²⁵I]IPPI and [¹²⁵I]IBETA binding in autoradiographic images were significantly higher in DSAD and AD gray matter (GM) compared to CN. When comparing DSAD with AD, FCX and TCX GM binding was similar throughout DSAD and AD, except in FCX GM where there was 48% more [¹²⁵I]IPPI binding in DSAD than AD. In vitro drug inhibition studies revealed that [¹²⁵I]IPPI binding was significantly inhibited with increasing harmine concentrations (IC₅₀ = 115 nM) in DSAD FCX and TCX, but KuFal194, a DYRK1A drug, minimally inhibited [¹²⁵I]IPPI binding in the same cases. The GM/white matter ratios for DSAD ([¹²⁵I]IPPI = 4.1, [¹²⁵I]IBETA = 2.9) and AD ([¹²⁵I]IPPI = 4.2, [¹²⁵I]IBETA = 2.6) were significantly greater than CN ([¹²⁵I]IPPI = 1.3, [¹²⁵I]IBETA = 1.2). A positive correlation between [¹²⁵I]IPPI and [¹²⁵I]IBETA binding suggests a synergistic relationship between tau and Aβ plaque in DSAD and AD pathology. This study demonstrates that [¹²⁵I]IPPI and [¹²⁵I]IBETA may serve as novel radiotracers in both DSAD and AD to continue diagnostic investigations.

Objective: This study aims to explore the role of ubiquitination in neuroinflammation and functional damage after stroke using multi-omics analysis, focusing on the pathways influenced by ubiquitination.

Methods: Gene expression data related to stroke were collected from the GEO database. Differentially expressed genes were identified using the "limma" package in R. GO and KEGG enrichment analyses were performed to identify significant pathways. Ubiquitination data were integrated with differential gene data to identify genes with ubiquitination sites, focusing on those that bind to E3 ligases. Network analysis was conducted to examine the interactions among ubiquitin-modified proteins, and protein-RNA correlations were analyzed using data from proteomic analysis.

Results: The analysis identified several inflammatory pathways significantly altered after stroke, including the NF-κB, TNF, and NOD-like receptor signaling pathways. A total of 113 genes with ubiquitination sites were found to be associated with E3 ligases and stroke-related genes. Among them, TRIM37 and TRIM25 emerged as key regulatory factors. Protein interaction network analysis revealed that ubiquitination modifications enhance neuroinflammation, leading to functional impairments. Post-translational modifications, indicated by higher protein stability, were observed in the proteins with the most ubiquitination sites, supporting their potential as therapeutic targets.

Discussion: The study identifies TRIM37 and TRIM25 as crucial regulators of neuroinflammation through ubiquitination after stroke. These findings suggest that ubiquitination plays a significant role in stroke pathology and could serve as therapeutic targets for stroke treatment.