BackgroundEyeblink conditioning is a canonical model of associative motor learning and has played a central role in theories of cerebellar plasticity. Purkinje cells occupy a central position in this circuit, receiving conditioned and unconditioned stimulus-related inputs and providing the sole output of the cerebellar cortex. However, the cellular mechanisms by which Purkinje cells contribute to the acquisition, timing, expression, and extinction of conditioned eyeblinks remain debated.MethodsWe systematically reviewed animal studies investigating Purkinje cell mechanisms in eyeblink conditioning to summarize the experimental approaches used in the field, extract qualitative and quantitative evidence, and identify theoretical trends and methodological limitations. A PubMed search identified 184 records, of which 74 met the inclusion criteria. Included studies were classified according to publication features, animal model, conditioning protocol, intervention type, Purkinje cell-related physiological or structural measurements, and proposed learning mechanism.ResultsMost studies either manipulated Purkinje cell function or measured Purkinje cell-associated physiological or structural properties, but only three combined both approaches, revealing a major separation between interventional and physiological evidence. Genetic interventions were predominantly performed in mice, whereas direct Purkinje cell physiological or structural measurement studies were more commonly based on electrophysiological recordings and showed greater model heterogeneity. Most conditioning protocols used parameters compatible with acquisition, although essential details such as interstimulus interval, intertrial interval, or trial number were incompletely reported in a subset of studies. When grouped by publication period, the reviewed studies showed a shift from LTD-centred explanations toward more diverse models that incorporate intrinsic excitability, Purkinje cell pause responses, inhibitory microcircuit mechanisms, cerebellar nuclear plasticity, and olivo-cerebellar feedback.DiscussionThese findings suggest that Purkinje cell contributions to eyeblink conditioning cannot be reduced to a single plasticity mechanism. Instead, the literature supports a multi-level model in which synaptic, intrinsic, and circuit mechanisms jointly shape learning, while also revealing substantial gaps in cross-species validation, reporting quality, and studies combining cell-specific intervention with direct physiological measurement.
Immaturity of neurons in the adult hippocampal dentate gyrus (DG) has been implicated in the pathophysiology of neuropsychiatric disorders. Pseudo-immaturity of DG neurons can be induced by neuronal hyperexcitation in adulthood. This “dematuration,” a reversal of maturation, could lead to aberrant neuronal maturation, if activated during development. However, it has not been directly tested whether dematuration can be induced in developing neurons. In the present study, we examined the effect of electroconvulsive treatment (ECT) on DG neurons of mice at several different developmental stages. Electrophysiological recordings were made using hippocampal slices. We analyzed frequency facilitation, a form of short-term synaptic plasticity, at the DG output mossy fiber synapses as an index of functional maturity of DG neurons. ECT had no significant effects on mossy fiber synaptic transmission at early postnatal ages, but it significantly reduced frequency facilitation at the postnatal age of ≥4 weeks, suggesting the induction of dematuration. Neuronal maturation marker analysis confirmed this result. The development of responsiveness to ECT was accompanied by maturation of N-methyl-D-aspartate receptor functions at the excitatory synaptic input onto DG neurons. Our results demonstrate that neuronal dematuration by ECT becomes inducible in postnatal 4 weeks in the DG of mice. Neuronal hyperexcitation such as seizures or alterations in N-methyl-D-aspartate receptor signaling around this developmental stage might affect proper maturation of DG neurons, thereby possibly increasing a risk of neuropsychiatric disorders.
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.
