Search Results (205)

α-Synuclein (α-Syn) is a key presynaptic protein, primarily known for its role in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, including dementia with Lewy bodies (DLB). Although much of the research has focused on the nigrostriatal dopamine (DA) pathway, there is growing recognition that the accumulation of misfolded α-Syn in the prefrontal cortex (PFC) is a critical driver of non-motor symptoms and cognitive deficits in PD and DLB. This review examines the dual role of α-Syn in the PFC circuitry, initially exploring its regulation of synaptic vesicle (SV) dynamics and recycling to maintain stable neurotransmission. We highlight its contribution to the modulation of glutamatergic (Glu) and GABAergic (γ-aminobutyric acid, GABA) synapses, which ensures the functional excitatory/inhibitory (E/I) balance of prefrontal circuits. Conversely, in PD and DLB, the transition of functional α-Syn monomers to pathological oligomers triggers a cascade of synaptic failures. We analyze how α-Syn aggregation causes pathology in dendritic spines, leads to a progressive reduction in the density of synaptic markers, and impairs cortical plasticity. Synthesizing evidence from neuroimaging studies, post-mortem human cortical samples, and animal models, this review emphasizes the PFC as a vulnerable brain region where α-Syn-mediated synaptic dysfunction translates into cognitive and emotional deficits. Deciphering these early synaptic alterations is essential for developing neuroprotective strategies that preserve cortical function in PD and DLB. Full article

Breast cancer brain metastasis (BCBM) affects up to 30% of patients with metastatic disease and carries a median survival of only 4–18 months. Emerging evidence reveals that BCBM cells are not passive survivors, but active participants that hijack core neurotransmitter networks, GABA (gamma-aminobutyric acid) and glutamate, to fuel their growth. BCBM, particularly triple-negative breast cancer (TNBC), frequently switch to a GABAergic mode utilizing brain-derived GABA as an oncometabolite. In parallel, BCBM cells can also form direct synapses with neurons, tapping into excitatory input through glutamatergic receptors to drive tumor cell proliferation and survival. Concurrently, reprogrammed astrocytes establish gap junctions, secrete growth factors, and provide metabolic support. Together, tumor cells, neurons, and astrocytes form a pathological partnership locked in feedback loops sustaining metastatic progression. This review focuses on the unique mechanisms employed by distinct breast cancer subtypes and maps the metastatic progression from pre-metastatic to mature brain metastatic niche formation of BCBM. We highlight opportunities to repurpose neurological drugs to disrupt these communication axes. Full article

Opioid analgesics are essential in the management of severe and chronic pain; however, their prolonged use is limited by the onset of analgesic tolerance and opioid-induced hyperalgesia (OIH). Recent studies increasingly implicate both synaptic functional and structural plasticity within nociceptive pathways as crucial mechanisms in OIH and tolerance. This review integrates current mechanistic understanding of how opioids alter synaptic transmission throughout the dorsal root ganglia (DRG), spinal dorsal horn, and supraspinal nociceptive networks. Peripherally, μ-opioid receptor (MOR) activation on TRPV1-positive nociceptors initiates presynaptic long-term potentiation (LTP), forming an early substrate for central sensitization. In the spinal dorsal horn, chronic opioid exposure drives NMDAR-dependent LTP, TRPC-mediated calcium influx, and actin cytoskeleton remodeling, leading to persistent increases in synaptic strength and excitatory connectivity. In supraspinal regions—including the ventral hippocampus, prefrontal cortex, and amygdala—opioids promote experience-dependent plasticity and predictive coding, which link environmental cues to reduced analgesic effectiveness. In addition to synaptic functional plasticity, opioid-induced synaptic structural plasticity within nociceptive pathways has been shown to underlie the long-term nature of opioid analgesic tolerance. Collectively, these data define a distributed network of opioid-responsive synapses whose pathological potentiation underpins the development of tolerance and hyperalgesia. Elucidating these mechanisms underlying OIH and tolerance paves the way for targeted therapeutic strategies that maintain analgesic efficacy while minimizing adverse synaptic remodeling and negative outcomes. Full article

Amygdala dysfunction is implicated in stress-related affective disorders, and astrocytes are key regulators of amygdalar neuroplasticity. Here, we examined whether running exercise modulates astrocyte number, morphology, proliferation, and excitatory synaptic contacts in the basolateral amygdala (BLA) and central amygdala (CeA) in rats exposed to chronic unpredictable stress (CUS). Anhedonia-like behaviors were evaluated using the sucrose preference test, while anxiety-related behaviors were assessed using the elevated plus maze and open field tests. Unbiased stereological three-dimensional quantification was used to assess amygdalar volume and estimate astrocyte numbers in BLA and CeA, and immunofluorescence with morphological reconstruction was performed to quantify astrocytic complexity, proliferation, and astrocyte-associated PSD95⁺ puncta. Running exercise significantly increased sucrose preference in CUS rats, whereas elevated plus maze and open field measures were not significantly changed. CUS reduced astrocyte number and proliferation, and induced astrocytic morphological atrophy in both subregions. These alterations were reversed by running. Moreover, running increased the number of excitatory synapses contacted by astrocytes in the BLA and CeA of CUS rats. These findings suggest that running promotes astrocyte-mediated structural remodeling in amygdalar subregions, which may contribute to the regulation of anhedonia-like behavioral alterations associated with chronic stress. Full article

Animal studies have shown that early life exposure to general anesthetics may impair brain development. However, the implications of this phenomenon in human patients remain unclear. In this study, we use an induced pluripotent stem cell (iPSC)-derived human brain microphysiological system (bMPS) to investigate the effects of early sevoflurane (SEV) exposure on human brain development. Human iPSCs were cultured and differentiated into neural progenitor cells (NPCs) and then into bMPS. At week 8, bMPSs were exposed to 2.4% SEV for 4 h. Four weeks after exposure, immunofluorescence (IF), Western blotting (WB), and quantitative real-time polymerase chain reaction (qPCR) were conducted to evaluate the alteration of nerve cells in bMPS. After SEV exposure, the number of apoptotic cells increases, and the level of neural differentiation markers decreases. The ratios of mature neurons over NPCs and mature oligodendrocytes over oligodendrocyte progenitor cells (OPCs) are reduced, which leads to a reduction in myelination. SEV also impedes the development of astrocytes and synaptogenesis, especially the formation of excitatory synapses. Meanwhile, SEV increases the expression of molecules in the mammalian target of rapamycin (mTOR) signal pathway. In conclusion, early SEV exposure substantially disrupts the development of human brain tissue, and the mTOR signal pathway is likely to be involved in this alteration. Full article

Mitochondrial Ca²⁺ signaling is increasingly recognized as a key integrator of synaptic activity, metabolism, and redox balance within the tripartite synapse. At excitatory synapses, Ca²⁺ influx through ionotropic glutamate receptors and voltage-gated channels is sensed and transduced by strategically positioned mitochondria, whose Ca²⁺ uptake and release tune tricarboxylic acid cycle activity, adenosine triphosphate synthesis, and reactive oxygen species (ROS) generation. Through these Ca²⁺-dependent processes, mitochondria are proposed to help set the threshold at which glutamatergic activity supports synaptic plasticity and homeostasis or, instead, drives hyperexcitability and excitotoxic stress. Here, we synthesize how mitochondrial Ca²⁺ dynamics in presynaptic terminals, postsynaptic spines, and perisynaptic astrocytic processes regulate glutamate uptake, recycling, and release, and how subtle impairments in these pathways may prime synapses for failure well before overt energetic collapse. We further examine the reciprocal interplay between Ca²⁺-dependent metabolic adaptations and glutamate homeostasis, the crosstalk between mitochondrial Ca²⁺ and ROS signals, and the distinct vulnerabilities of neuronal and astrocytic mitochondria. Finally, we discuss how disruption of this Ca²⁺-centered mitochondria–glutamatergic axis contributes to synaptic dysfunction and circuit vulnerability in neurodegenerative diseases, with a particular focus on Alzheimer’s disease. Full article

Neuronal synapses are the functional units of communication in the central nervous system. This review describes the molecular mechanisms regulating synaptic transmission, plasticity, and circuit refinement. At the presynaptic active zone, scaffolding proteins including bassoon, piccolo, RIMs, and munc13 organize vesicle priming and the localization of voltage-gated calcium channels. Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1. Following exocytosis, synaptic vesicles are recovered through clathrin-mediated, ultrafast, bulk, or kiss-and-run endocytic pathways. Postsynaptically, the postsynaptic density (PSD) serves as a protein hub where scaffolds such as PSD-95, shank, homer, and gephyrin anchor excitatory (AMPA, NMDA) and inhibitory (GABA-A, Glycine) receptors are observed. Synaptic strength is modified during long-term potentiation (LTP) and depression (LTD) through signaling cascades involving kinases like CaMKII, PKA, and PKC, or phosphatases such as PP1 and calcineurin. These pathways regulate receptor trafficking, Arc-mediated endocytosis, and actin-dependent remodeling of dendritic spines. Additionally, synapse formation and elimination are guided by cell adhesion molecules, including neurexins and neuroligins, and by microglial pruning via the complement cascade (C1q, C3) and “don’t eat me” signals like CD47. Molecular diversity is further expanded by alternative splicing and post-translational modifications. A unified model of synaptic homeostasis is required to understand the basis of neuropsychiatric and neurological disorders. Full article

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article

Exercise training reduces metabolic dysfunction and improves neural function; however, its cortical molecular effects in diabetic–obese conditions remain unclear. Here, we aimed to identify transcriptional pathways by integrating physiological evaluation with an in silico analysis of cortical RNA-seq data from Zucker Fatty Diabetes Mellitus rats following a 12-week swimming training program. Exercise training reduced body weight and improved glucose control and blood pressure. RNA-seq analysis revealed 814 differentially expressed genes, with pathway enrichment highlighting glutamatergic synapse, retrograde endocannabinoid signaling, and oxytocin signaling pathways. These coordinated transcriptional shifts involved genes related to excitatory neurotransmission, neuromodulatory feedback, and calcium-dependent regulation. As hypothesis-generating models, these pathway-level patterns suggest that exercise training may modulate cortical signaling properties in diabetic–obese states and provide a conceptual framework for future mechanistic investigation. Full article

Optoelectronic synapses based on transition metal dichalcogenides have received much attention as artificial synapses due to their good stability in the air and excellent photoelectric properties; however, they suffer from ultraviolet light-triggered synapses due to the ultraviolet insensitivity of transition metal dichalcogenides. In this paper, an ultraviolet-enhanced artificial synapse was achieved on WSe₂ combined with SrAl₂O₄: 6% Eu²⁺, 4% Dy³⁺ phosphor. The strong ultraviolet absorption of SrAl₂O₄: 6% Eu²⁺, 4% Dy³⁺ phosphor and radiation reabsorption are responsible for the ultraviolet-enhanced response of the WSe₂-SrAl₂O₄ synapse. The excitatory post-synaptic current of the WSe₂-SrAl₂O₄ synapse triggered by a single pulse at 365 nm was enhanced 4 times more than that from 2D WSe₂, while the decay time of the post-synaptic current was 9.7 times longer than those from the WSe₂ device. The excellent ultraviolet sensitivity and decay time promoted the good regulation of the synaptic plasticity of the WSe₂-SrAl₂O₄ device in terms of power densities, pulse widths, pulse intervals, and pulse numbers. Furthermore, outstanding learning behavior was simulated successfully with a forgetting time of 25 s. Handwritten digit recognition was realized with 96.39% accuracy, based on the synaptic weight of the WSe₂-SrAl₂O₄ synapse. This work provides a new pathway for ultraviolet photoelectric synapse and brain-inspired computing. Full article

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, characterised by the build-up of amyloid beta (Aβ) plaques and neurofibrillary tangles comprising hyper-phosphorylated tau. Increasing evidence indicates that in the early stages of AD, elevated levels of oligomeric forms of Aβ and phosphorylated tau (p-tau) gives rise to impaired synaptic function which ultimately drives AD-associated cognitive abnormalities. Thus, developing drugs that can limit the synaptic impairments that occur early in AD may have therapeutic benefits. Clinical evidence increasingly supports a link between lifestyle choices and AD risk. Indeed, there is an association between the circulating levels of the metabolic hormone leptin, mid-life obesity and disease risk, which has in turn stimulated interest in targeting the leptin system to treat AD. It is well-established that leptin readily accesses the brain, with the hippocampus, a key region that degenerates in AD, identified as a prime target for this hormone. Within the hippocampus, leptin has cognitive enhancing properties as it markedly influences the cellular events underlying hippocampal-dependent learning and memory, with significant impact on synaptic plasticity and trafficking of glutamate receptors at hippocampal excitatory CA1 synapses. Moreover, studies using a range of cell-based systems and animal models of disease indicate not only that leptin has powerful pro-cognitive effects, but also that leptin protects against the unwanted synapto-toxic effects of Aβ and tau, as well as enhancing neuronal cell viability. Moreover, recent studies have demonstrated that smaller leptin-based molecules replicate the full repertoire of protective features of whole leptin. Here we review the evidence that the leptin system is a potential novel avenue for drug discovery in AD. Full article

Alzheimer’s disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5–2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke. Full article

We examined whether an increase in synaptic activity resulted in an increase in quantal size at the neuromuscular junction (NMJ) of third-instar Drosophila larvae. Spontaneous miniature excitatory postsynaptic currents (mEPSCs) or miniature excitatory postsynaptic potentials (mEPSPs) were recorded before and after nerve stimulation. We found that prolonged (60 s) or brief (1.25 s) nerve stimulation produced an increase in quantal size; this appears to be a general property of these synapses since it was seen at all four muscle fibers (MFs) used in this study. The effect was examined along Is and Ib terminals by expressing GCaMP in the MF membrane and examining postsynaptic Ca²⁺ signals produced by spontaneous transmitter release. The activity-dependent increase in quantal size occurred at both Is and Ib terminals, and the increase in frequency and amplitude of quantal events at individual synaptic boutons was correlated. Both the increase in quantal size and frequency were found to be dependent upon an increase in postsynaptic Ca²⁺, based on studies in which MFs were preinjected with the Ca²⁺ chelator BAPTA (1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid). To examine the effect of postsynaptic activity on glutamate sensitivity, we iontophoresed glutamate pulses at the NMJ and recorded the glutamate-evoked excitatory postsynaptic potentials (gEPSPs). Trains of glutamate pulses produced an increase in gEPSP amplitude; this potentiation was not seen when Ca²⁺ was eliminated from the bath or after inhibiting calmodulin or CaMKII. The activity-dependent increase in quantal size may result from an increase in postsynaptic sensitivity due to activation of CaMKII. Full article

The optimal computing ability of spiking neural networks (SNNs) mainly depends on the connection weights of their synapses and the thresholds that control the spiking. In order to realize the optimization calculation of different objective functions, it is necessary to modify the connection weights adaptively and make the thresholds dynamically self-learning. However, it is very difficult to construct an adaptive learning algorithm for spiking neural networks due to the discontinuity of neuron spike sending process, which is also a fatal problem in this field. In this paper, an efficient adaptive learning algorithm for spiking neural networks is proposed, which adjusts the weights of synaptic connections by a learning factor adaptively and adjusts the probability of spike sending by the self-organizing learning method of the dynamic threshold, so as to achieve the goal of automatic global search optimization. The algorithm is applied to the learning task of global optimization, and the experimental results show that this algorithm has good stability and learning ability, and is effective in dealing with complex multi-objective optimization problems of spatiotemporal spike mode. Moreover, the proposed framework explicitly leverages problem and model symmetries. In Traveling Salesman Problems, distance symmetry (d(i, j) = d(j, i)) and tour permutation symmetry are preserved by our spike-train-based similarity and energy updates, which do not depend on node labels. Together with the homogeneous neuron dynamics and balanced excitatory–inhibitory populations, these symmetry-aware properties reduce the effective search space and enhance the convergence stability. Full article

Background: Fragile X Syndrome (FXS) is the most common monogenic cause of autism spectrum disorders, and is characterized by the excessive immature excitatory synapses in cortical neurons, leading to excitatory/inhibitory imbalance and core autistic behaviors. This synaptic pathology has been attributed to dysregulated levels of synaptic proteins, including CYFIP2: a key regulator of synaptic structure and plasticity. However, the mechanism underlying the increased CYFIP2 protein level in FXS neurons remains unclear. Neurons abundantly secrete extracellular vesicles (EVs) enriched with bioactive cargos (proteins and miRNAs). Objectives: the goal of this research is to identify whether EV-dependent secretion plays important roles in regulating the intracellular CYFIP2 protein level in WT and FXS neurons. Methods and Results: our proteomic analysis reveals that CYFIP2 protein is packaged in EVs released by mouse cortical neurons. Pharmacological and genetic blockades of neuronal EV release significantly elevated intracellular CYFIP2 levels by 78 ± 14% and 168 ± 39%, respectively. Glutamate-evoked EV release significantly reduced the CYFIP2 level by 24 ± 2%. Neurons from Fmr1 KO mice, an FXS model, secreted significantly less EVs (46 ± 5%) than the wild type, and showed significantly elevated CYFIP2 (by 155 ± 31%). Evoking EV release in FXS neurons significantly lowered the intracellular CYFIP2 (by 53 ± 6%). Conclusions: these findings identify an EV-secretion-dependent mechanism that controls neuronal CYFIP2 level, implicating EV-mediated export in the regulation of synaptic protein homeostasis, synaptic remodeling, and FXS-associated synaptic deficits. Full article