Sleep disturbances are increasingly recognized as clinically relevant markers in the early detection of psychotic disorders among adolescents and young adults. These disturbances, including insomnia, circadian rhythm disruptions, parasomnias, and fragmented sleep, affect up to 70% of individuals at clinical high risk for psychosis, rising to 80% in fully developed schizophrenia. This review synthesizes current evidence on the relationship between sleep problems and early psychotic symptoms, emphasizing their potential as observable and possibly modifiable indicators of illness onset. Neurobiological mechanisms suggest overlapping pathways for both sleep problems and the development of psychotic symptoms involving dopaminergic, serotonergic, and hormonal dysregulation, which are additionally exacerbated by psychological factors such as stress, substance use, and poor sleep hygiene. Screening methods, such as self-report questionnaires, actigraphy, and polysomnography, have demonstrated utility in identifying individuals at risk. Furthermore, sleep-focused interventions, particularly cognitive behavioral therapy, show promise in alleviating both sleep and psychiatric symptoms. Despite methodological limitations of available research, including heterogeneous study designs and short follow-ups, sleep assessment can represent a low-cost, scalable tool for early intervention. Future research should prioritize longitudinal, multimodal studies and explore personalized, sleep-centered preventive strategies. Furthermore, sleep disorders could be considered not only as early signs of developing psychosis but also as a potential therapeutic target in psychosis prevention.
Silent synapses represent a unique class of synaptic connections that are non-functional at rest but possess the potential to become functional, serving as a critical reservoir for neural plasticity. Their activation mechanisms not only challenge traditional models of synaptic maturation but also provide novel insights into brain function regulation and disease pathology. This article provides a systematic review of the regulatory mechanisms underlying silent synapse activation, encompassing pre-synaptic calcium signaling-mediated vesicle cycling and active zone (AZ) optimization, post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) membrane insertion and post-synaptic density protein 95 (PSD-95) anchoring, Mg2+ blockade release by N-methyl-D-aspartate receptor (NMDAR), as well as synergistic integration of upstream signaling pathways. Additionally, it explores the roles of astrocytes, epigenetic modifications, ubiquitin-proteasome systems, and autophagy-lysosomal systems in multi-level regulatory processes. Notably, abnormal regulation of silent synapses exhibits two contrasting pathological patterns in diseases: “desilencing impairment” (e.g., Alzheimer’s disease, depression) and “abnormally excessive desilencing” (e.g., drug addiction, chronic pain), which establishes a theoretical framework for targeted interventions. The study further evaluates the applicability and limitations of emerging technologies—including high-resolution imaging, single-cell omics, optogenetics, and AI-driven brain-inspired computing—in silent synapse research, while systematically summarizing clinical advancements, current challenges, and future directions, aiming to inform both fundamental neuroscience studies and therapeutic interventions.
Obesity-driven synaptic dysfunction is increasingly recognized as a key mechanism linking metabolic disorders to neurodegenerative diseases. This review aims to explore the utility of zebrafish (Danio rerio) as a translational model to investigate these mechanisms and screen peptide-based therapeutic strategies. Owing to their optical transparency, genetic tractability, and suitability for high-throughput screening, zebrafish provide a powerful platform for studying neuronal circuitry and evaluating bioactive peptides in vivo. Current evidence on pathophysiological processes underlying obesity-related synaptic impairment, including central resistance to metabolic hormones, oxidative stress, and the chronic inflammatory state, which promotes persistent immune activation and neuroinflammation. In addition, the persistence of these disturbances in the organism can lead to dysfunctions and pathologies, such as Parkinson’s and Alzheimer’s diseases, both of which are discussed in more detail in this review. Also, particular emphasis is placed on the roles of glial cells and the gut–brain axis in modulating synaptic integrity. We highlight how cutting-edge technologies, such as live neural imaging and single-cell transcriptomics, are accelerating peptide discovery and mechanism-of-action studies in zebrafish. Furthermore, we discuss emerging therapeutic peptides such as GLP-1 analogs and BDNF-based molecules that modulate inflammatory pathways, restore insulin signaling, and enhance neuronal resilience. Collectively, the evidence positions zebrafish as a robust model not only for elucidating disease mechanisms but also for advancing peptide-based interventions targeting synaptic dysfunction in obesity.
Electrical brain stimulation has been used to treat epilepsy with therapeutic success, but without complete understanding of its cellular mechanisms of seizure suppression. Using acute human brain slices obtained from pharmaco-resistant epilepsy patients, we delivered high-frequency, high-intensity extracellular electrical stimulation while recording from neocortical layer 2/3 pyramidal neurons (PNs), fast-spiking interneurons (FSINs), and non-fast-spiking interneurons (nFSINs). Electrical stimulation led to an increasingly selective activation of FSINs at higher stimulation frequencies, which consistently fired with high fidelity throughout prolonged stimulation periods while both PNs and nFSINs were suppressed rapidly. In addition, stimulation caused a long-term rebalancing of synaptic weights through selective and differential depression of synaptic inputs, resulting in an approximately twofold increase in the normalized excitatory-to-inhibitory postsynaptic conductance at FSINs while not affecting PNs, thereby providing support for FSIN activation toward increased inhibitory tone and network stabilization. These stimulation-induced effects were accompanied by only minimal changes in neuronal intrinsic excitability.
Synaptic failure is one of the earliest and most significant contributors to the cognitive decline in Alzheimer’s disease (AD), preceding extensive neuronal loss. Although amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein characterize the disease, memory impairment primarily results from the gradual deterioration of synaptic communications. This decline is caused by a complex interaction among mitochondrial energy deficits, cytoskeletal instability, disrupted exosomal signaling, and immune-mediated synaptic pruning. Mitochondrial dysfunction, particularly affecting complexes I and IV, leads to reduced ATP production, faulty mitophagy and disrupted calcium (Ca2+) homeostasis, placing the synapse under constant metabolic stress. Elevated reactive oxygen species (ROS) further activate stress pathways, including p38 MAPK and JNK, contributing to synaptic protein damage and impaired long-term potentiation (LTP). Furthermore, tau hyperphosphorylation destabilizes the neuronal cytoskeleton, weakening dendritic spine integrity and synaptic connectivity. At the same time, Aβ alters the cargo carried by exosomes, facilitating the spread of pathogenic Aβ and tau species between the neurons and modulating microglial activation and complement-mediated synaptic pruning. Additionally, emerging studies highlight the role of NETosis in exacerbating neuroinflammation and compromising the blood-brain barrier (BBB) integrity, thereby increasing synaptic damage. In contrast, phytochemicals such as resveratrol, ginkgolide B, curcumin, ferulic acid, epigallocatechin gallate (EGCG), and quercetin exert neuroprotection by restoring redox balance, altering exosomal communications, stabilizing cytoskeletal signaling, and reducing neuroinflammation. Moreover, delivery techniques such as nanoparticles and engineered exosomes enhance BBB permeability and enable targeted synaptic intervention. Overall, this review summarizes current mechanistic findings and highlights the potential of phytochemicals as multitarget therapeutic agents for synaptic repair and functional recovery in AD.
ObjectiveImmediate postictal potentiation (PIP), a unique phenomenon observed in immature animals, may contribute to the enhanced sensitivity of young animals to seizures and epilepsy. PIP deserves more experimental attention because understanding its mechanisms could provide valuable insights into treating these conditions.MethodsUsing the technique of cortical afterdischarges (ADs), we analyzed the effect of glutamate receptor antagonists on PIP in 12-day-old rats. A conditioning AD was recorded, followed 1 min later by a test AD. Then, an antagonist was administered, and 10 min later, another pair of ADs was elicited.ResultsThe most pronounced effect was observed with ifenprodil, a selective antagonist of NMDA receptors that contain the GluN2B subunit, which is the dominant form in immature animals. This antagonist not only suppressed the immediate PIP but also converted the condition to an adult-like postictal depression. Post-drug, the test AD was significantly shorter than the conditioning AD. Less pronounced effects were found with non-selective NMDA antagonists, antagonists that preferntially target NMDA receptors containing the GluN2A subunit (which is the dominant form in adult animals), or metabotropic glutamate receptor antagonists. In contrast, AMPA antagonists had their major effects on delayed PIP. This was particularly true for IEM 1460, a selective antagonist of AMPA receptors that lack a functional GluR2 subunit, which is again a form predominant in immature animals.ConclusionPIP appears to be a function of the unique structure of glutamate receptors in the immature nervous system, particularly NMDA receptors.HighlightsPostictal potentiation (PIP) rather than depression is observed in immature rats.Two types of PIP are identified—immediate (up to 5 min) and delayed.Immediate PIP is due to NMDA receptors containing the NR2B subunit.Delayed PIP is a more complicated phenomenon. Among systems participating in delayed PIP, AMPA receptors play a role.
Introduction:Ambient glutamate is capable of regulating neural excitability and contributes to several brain pathologies. It is well established by experiments on rodent tissue that extrasynaptic glutamate -mainly regulated by astrocytic glutamate uptake- can elicit both phasic slow inward currents (SICs) and tonic inward currents. These currents are thought to be mediated by overlapping mechanisms and receptors; and exist under physiological conditions. SICs were also found in the human neocortex but the existence of the tonic inward currents and their relationship with SICs have not been demonstrated yet. Methods:We aimed to investigate tonic inward currents and their relation to slow inward currents (SICs) elicited by the inhibition of glutamate transport in the human neocortex. Brain samples removed for accessing the primary brain tumors or metastases were collected from patients with broad age range. Slice electrophysiological approach and post-hoc morphological analysis was used. Results:We found that inhibition of the EAAT transporters by DL-TBOA elicited both SICs and tonic inward currents. The tonic current was only partially reverted by the GluN2B subunit specific NMDA receptor (NMDAR) antagonist ifenprodil, whereas SICs were almost fully eliminated. The amplitude of the current was inversely proportional with the age of the patient and disappeared in elderly over the age of 70. The charge transfer of SICs per minute was directly proportional with the magnitude of the tonic inward current. Omitting magnesium from the recording solution or application of the EAAT positive allosteric modulator GT949 did not elicit any notable tonic current. Discussion:In summary, NMDAR-dependent tonic inward currents are overlapping but partially separable phenomena from SICs. One might hypothesize that the tonic current is only present under excitotoxic conditions and do not determine physiological neuronal excitability in human.
Synapses are the basic unit of information transfer between neurons. Their dysfunction is a common trigger of cognitive diseases and disorders. However, high-throughput analysis methods to assess synaptic function and dysfunction are lacking. Calcium imaging in cultured neurons in the absence of Mg2+ and presence of TTX allows visualization of NMDAR-dependent spontaneous synaptic calcium transients, which report pre and postsynaptic function. Here, we introduce a high-throughput automated analysis pipeline that combines Suite2p ROI detection and Python scripts to analyze tens of thousands of synapses and quantify changes in presynaptic vesicle fusion rates (frequency), postsynaptic function (amplitude), and the number of functional synapses. We use this pipeline to test known NMDAR agonists (glycine) and antagonists (ketamine, memantine, APV), presynaptic function modulating compounds (PDBu), and encephalitis patient-derived NMDAR auto-antibodies, where our pipeline proved more sensitive in detecting dysfunction at the single-synapse level than other methods. The ability to detect, track, and quantify activity across tens of thousands of synapses and millions of synaptic calcium transients using this pipeline will aid drug discovery of compounds that protect synapse function.
Motor neuron disease (MND) is marked by progressive neurodegeneration in which presynaptic Ca2+-handling and mitochondrial metabolism are thought to be vulnerable, but direct functional studies in human brain are scarce because most material is frozen long-term. Here, we show that synaptosomes isolated from paired fresh and experimentally frozen mouse cortex, and from cryopreserved human motor cortex, retain recognisable synaptosome ultrastructural features, synaptic proteome enrichment, and depolarisation-evoked Ca2+-mobilisation. K+ and veratridine elicited robust, pharmacologically suppressible Ca2+ influx across preparations, and response amplitudes in human samples varied by region but did not correlate with donor age, post-mortem interval (PMI), or years in storage. Synaptosomes from neuropathologically confirmed MND motor cortex and hSOD1G93A mouse cortex showed significantly greater depolarisation-evoked Ca2+ entry than their respective controls, suggesting that increased presynaptic Ca2+ influx is shared across our human MND cohort and the hSOD1G93A mouse model. Using synaptosome preparations from MND and control motor cortices in Seahorse respiratory assays, we found that Complex IV-driven oxygen consumption (TMPD/ascorbate-evoked and azide-sensitive) was reduced in MND synaptosomes, whereas donor-matched free-mitochondrial fractions showed no group difference, supporting a Complex IV defect detectable in the synaptosome-enriched fraction within this cohort. By defining protein-to-OCR relationships for both fractions, we provide practical parameters for applying these assays to archived human cohorts. Together, these data suggest that archived cryopreserved human brain tissues can support informative synaptosome Ca2+ and bioenergetic readouts, and that synaptosome-enriched preparations may reveal disease-relevant presynaptic phenotypes in MND that are not evident in donor-matched bulk mitochondrial isolates.
IntroductionThe amygdala is involved in processing and memory of emotional stimuli. The cortical regions of the amygdala are situated medially to the piriform cortex (PC) and are also considered part of the olfactory system, which may explain why scents can evoke strong emotional responses and trigger vivid memories. Similarly to the PC, the anterior cortical nucleus of the amygdala (ACo) is a three-layered structure receiving direct input from the main olfactory bulb (MOB) through the lateral olfactory tract (LOT), without a thalamic relay. While activity processing, plasticity and behavioral relevance of the PC have been extensively studied, evidence on the functional properties of the olfactory amygdala is scarce. ACo participates in the innate response to aversive stimuli and could be involved in olfactory emotional learning. Primary cortices of different sensory modalities display early periods in which afferent connections are particularly plastic, and this is crucial for network maturation. Here, we studied the plastic properties of LOT-ACo synapses during olfactory system maturation, by assessing long-term potentiation (LTP) induction during the first weeks of life.MethodsWe performed field recordings of LOT-ACo synaptic potentials in brain slices from rats of 6 to 35 postnatal days (P6-P35) to assess LTP induction by theta-burst stimulation. To investigate if the developmental regulation of plasticity can be altered by early sensory deprivation, we performed unilateral naris occlusion.ResultsWe found that LTP was significantly higher between P16-P25 (reaching ~30%) compared to earlier or later stages. Interestingly, LTP was missing around the end of the first postnatal month (P26-35). Furthermore, we demonstrated that LTP induction at one month of age was recovered in both hemispheres in rats that were subjected to unilateral sensory deprivation.DiscussionThis result suggests the existence of a critical period for LTP induction in olfactory connections to the amygdala. Therefore, ACo may not only be involved in innate responses to biologically relevant odorants, but could also participate in early experience-dependent associative learning. Moreover, olfactory deprivation could extend the critical period for plasticity, making the system prone to undergo plastic changes at later developmental stages.
Late preterm birth, occurred between 34 and 36 weeks of gestation, constitutes a risk factor for neurodevelopment. Despite being initially considered as a near term group of newborns, late preterm infants have shown dysfunctions in cerebral connectivity and in learning at school age. This mini-review will summarize key findings of latest studies about altered brain connectivity and cognition in this clinical population. The present work will also discuss current research gaps and brain-behavior relationships. The main objective is to contribute to optimize further investigation on the field and early intervention strategies.
Experience reshapes cortical circuits, yet plasticity is tightly gated—high during early critical periods and increasingly constrained with maturation. Later in life, aging and Alzheimer’s disease (AD) create a growing demand to restrain network hyperactivity. Across these contexts, excitatory drive onto parvalbumin-positive fast-spiking interneurons (PVs)—shaped by synaptic organizers such as NPTX2—offers a control point for tuning inhibitory tone while preserving fast, precise inhibition. We outline the cellular and synaptic specializations that make PVs powerful regulators of network excitability, then synthesize evidence from visual cortex suggesting that critical period termination reflects the loss of plasticity at principal neuron→PV inputs. Finally, we extend this framework to aging and AD, where medial temporal lobe hyperactivity and early PV dysfunction coincide with NPTX2 dysregulation, suggesting that restoring excitatory recruitment of PVs may help stabilize circuits and prevent cognitive decline.
Introduction:In the mammalian cochlea, hearing relies on highly specialized ribbon-type synapses between sensory inner hair cells (IHCs) and postsynaptic spiral ganglion neurons. During early postnatal maturation, structural and functional refinements re-shape synaptic morphology and thereby maximize release efficiency in the run-up to hearing onset. This developmental period is further characterized by the occurrence of pre-sensory spontaneous activity waves, which are essential for the functional maturation of the ascending auditory pathway- yet, their importance for IHC presynaptic structural refinement remains uncertain. Methods:To investigate activity-dependent structural plasticity at cochlear ribbon synapses, we combined genetic, pharmacological, and optogenetic approaches with immunohistochemical and electrophysiological analyses. Moreover, we developed a novel optical stimulation device (OSD) that enables millisecond-precise, long-term and differentially-patterned optogenetic activation of cochlear IHCs under tightly controlled conditions within a standard tissue culture incubator. Results:Using this experimental framework, we show that positive as well as negative activity modulation triggers dynamic and rapidly-inducible homeostatic scaling of ribbon synapse morphology. Moreover, our data indicate that the temporal pattern of the presynaptic activity acts as a fundamental regulatory component of this process. Discussion:Our results suggest that - prior to hearing onset - pre-sensory synaptic activity plays a critical role in shaping cochlear ribbon synapse architecture in the developing auditory system.
Studying human cortical physiology requires access to viable brain tissue, yet species-specific differences limit the translational value of animal models. To address this, multiple laboratories have developed ex situ approaches for investigating neurosurgical access tissue using electrophysiological, molecular, and imaging techniques. Here, we introduce the Freiburg framework—a structured, multimodal approach that integrates high-resolution electrophysiology, advanced imaging, molecular analyses, and Raman microscopy to assess neuronal and glial function under controlled, near-native conditions. Clinical metadata, including preoperative MRI, together with in-patient controls is systematically incorporated to account for biological variability and to enable human-to-human translational (H2H) comparisons. The framework further enables controlled neuromodulatory and pharmacological interventions, including ex situ repetitive transcranial magnetic stimulation (rTMS). By formalizing an end-to-end experimental pipeline, the Freiburg framework supports systematic investigation of human-specific neurophysiological mechanisms and provides a robust foundation for translational human neuroscience.
In vitro maintained human brain slices provide a unique experimental platform for investigating rhythmic neuronal network activity, bridging the gap between animal models and clinical studies. A wide range of spontaneous and induced oscillatory activities has been described in human brain slices. However, their occurrence and characteristics are strongly shaped by methodological determinants spanning tissue origin, slice preparation, recording conditions, and induction strategies. This has been shown to have a profound impact on the reproducibility and interpretation of oscillatory dynamics. This review synthesizes current evidence on rhythmic network activity in acute human brain slices, with a particular emphasis on how methodological determinants interact with intrinsic circuit properties to generate oscillatory dynamics. We discuss how different experimental manipulations influence oscillation frequency, stability, and spatial organization. We further examine the cellular and circuit mechanisms underlying rhythmic activity, highlighting the roles of excitatory–inhibitory balance, synaptic dynamics, neuromodulatory influences, and distinct interneuron populations. Finally, we consider how oscillatory patterns differ across disease contexts, particularly epilepsy and tumor-associated cortex, and discuss the translational value and limitations of human brain slices for linking microcircuit mechanisms to pathological and functional brain states.
Introduction:Programmed axon degeneration significantly affects neural connectivity, however, the underlying mechanisms remain poorly understood, particularly in cortical regions. Sterile Alpha and TIR motif-containing protein 1 (SARM1) is a known regulator of axon degeneration in the peripheral nervous system, but its role in cortical axon plasticity, particularly during injury conditions, remains unclear. This study examined the role of SARM1 in synaptic connectivity and remodelling in the adult sensory-motor cortex under normal physiological conditions and following acute axonal injury. Methods:Adult male Thy1-GFP-M mice (3-12 months) expressing EGFP in excitatory neurons were also either wild-type (WT-GFP) or null for SARM1 (SARM1KO-GFP). Using in vivo multiphoton microscopy, long cortical axon segments (~335 μm ± 140 μm), with terminaux and en passant synaptic boutons in the upper layers of the cortical neuropil, were repeatedly imaged at 48-h intervals to assess axon morphology, synaptic density, and synaptic turnover in the presence and absence of SARM1. Results:Without injury, axon morphology, synaptic density, and turnover were similar between WT and SARM1KO groups, suggesting that SARM1 is not necessary for maintaining baseline cortical synaptic connectivity. Following axotomy by laser lesion, the non-degenerating proximal axon (still connected to the soma) showed significant changes in synaptic plasticity, with an increased rate of loss of synapses. Discussion:Our findings suggest that SARM1 plays no role in the remodelling of synapses in the proximal axon after an acute axonal injury.
