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 (GABAARs), 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 GABAAR trafficking contributes to epileptogenesis and pharmacoresistance, particularly during severe conditions such as status epilepticus. Understanding the molecular mechanisms regulating GABAAR 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 GABAAR biogenesis within the broader framework of synaptic organization relevant to epilepsy and other neurological disorders.

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.

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.

Though the nucleus accumbens (NAc) is a key terminal region of the mesolimbic dopaminergic system, it is also innervated by noradrenergic inputs from the ventral medulla and contains intrinsic cholinergic neurons. However, the roles of α-adrenoceptors in regulating basal accumbal cholinergic activity remain unclear. This study employed in vivo microdialysis in unanesthetized rats to investigate the role of α1- and α2-adrenoceptors in modulating extracellular acetylcholine (ACh) levels in the NAc. Accumbal administration of the α2-agonist UK 14304 (30.0 and 300.0 pmol) and the α2-antagonist RX 821002 (0.6, 600.0, and 6000.0 pmol) dose-dependently decreased and increased accumbal ACh efflux, respectively. Neither compound (UK 14304: 300.0 pmol; RX 821002: 6000.0 pmol) affected basal accumbal dopamine levels. Co-administration of RX 821002 (0.6 pmol) blocked the UK 14304 (300.0 pmol)-induced reduction in ACh efflux, whereas UK 14304 (30.0 pmol) inhibited the RX 821002 (6000.0 pmol)-induced increase. Intraperitoneal administration of RX 821002 (1.0 mg/kg), but not UK 14304 (2.5 mg/kg), increased accumbal ACh efflux, which was inhibited by intra-accumbal infusion of UK 14304 (30.0 pmol). Neither the α1-agonist methoxamine (0.24 pmol) nor the α1-antagonist prazosin (6.0 pmol) altered accumbal ACh levels. Doses of drugs infused indicate the total amount (mol) during the 60-min infusion. These findings indicate that RX 821002 enhances ACh efflux in the NAc by blocking accumbal α2-adrenoceptor-mediated inhibition of ACh release. Given that reduced accumbal ACh levels have been implicated in cognitive impairment, systemic administration of α2-adrenoceptor antagonists should be investigated for their potential to improve such deficits in experimental models.

A quantitative description of the adenosine and caffeine influence on the glutamatergic synaptic neurotransmission is presented. The analysis is based on a set of coupled mathematical models for a sequence of processes involved in the synaptic transmission, starting from the action potential at the presynaptic axonal terminal and up to the spike generation at the postsynaptic membrane. Adenosine and caffeine act via binding to the presynaptic adenosine receptors that results in the alteration of axon terminal calcium ion influx and, thereby, in the modulation of the efficiency of neurotransmitter release. Dynamics of the glutamate in the synaptic cleft were determined taking into account its release from the presynaptic vesicles with subsequent glutamate diffusion and reuptake. Maximal value of the glutamate concentration in the cleft is about 1.2 mM. The glutamate content elevation induces a spike at the postsynaptic neuron. The dependence of the synaptic transmission efficiency on the levels of adenosine and caffeine has been analyzed. The probability of the synaptic transmission is increased from 0.3 to about 0.5 when varying caffeine concentration from 0 to 200 µM. Transmission probability significantly depends on the number of the postsynaptic glutamate receptors.

Non-motor symptoms in Parkinson's disease (PD) may be influenced by the α4β2* subtype of nicotinic acetylcholine receptors (nAChRs) present in the hippocampus (HP) and subiculum (SUB). To continue efforts in positron emission tomography (PET) diagnostics for PD, autoradiographic [18F]nifene binding to α4β2* nAChR was quantitatively assessed in the HP-SUB of PD (n = 27; 14 males and 13 females) and cognitively normal (CN) (n = 32; 16 males and 16 females) cases. Anti-ubiquitin for Lewy body and anti-α-synuclein immunostaining on adjacent slices were analyzed in QuPath, and [18F]nifene binding was quantified in OptiQuant. The SUB had greater [18F]nifene binding (51%-85%) compared to HP in all cases. Significantly higher [18F]nifene binding (>250%; p < 0.0001) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD = 3.53, whereas CN = 1.33, a >150% increase in PD (p < 0.0001). Binding of [18F]nifene to GM was >250% greater than WM in PD for both male and female. Male CN exhibited an increase, whereas male PD exhibited a significant decrease in [18F]nifene binding with aging, whereas females did not exhibit significant differences. In summary, α4β2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.

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.

A complete human sleep consists of multiple states, each of which has its own unique and typical characteristics. A clear definition of these states lays a solid foundation for the study of related sleep disorders. However, there remain significant challenges in current research on human sleep. Focusing on the automatic staging of sleep states, this review is organized around the technical route, technical challenges, and future perspectives of sleep staging. First, 2044 records related to sleep staging were initially screened from the Web of Science Core Collection, and key methodological themes were identified through an initial screening. Second, more than 200 highly relevant studies were selected for review, and 174 of them were cited. Compared with previous surveys on automated sleep staging, in this paper, more attention is paid to the complete technical route, key technical challenges, data strategy, and future research trends. Special attention is given to the N1 stage, which represents the most challenging classification target due to both its inherent physiological ambiguity and low inter-scorer reliability under the current AASM framework. This review aims to provide a practically oriented and operationally actionable reference for researchers in the field.

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.

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 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 [[125]I]IPPI binding to tau and [[125]I]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, [[125]I]IPPI and [[125]I]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 [[125]I]IPPI binding in DSAD than AD. In vitro drug inhibition studies revealed that [[125]I]IPPI binding was significantly inhibited with increasing harmine concentrations (IC50 = 115 nM) in DSAD FCX and TCX, but KuFal194, a DYRK1A drug, minimally inhibited [[125]I]IPPI binding in the same cases. The GM/white matter ratios for DSAD ([[125]I]IPPI = 4.1, [[125]I]IBETA = 2.9) and AD ([[125]I]IPPI = 4.2, [[125]I]IBETA = 2.6) were significantly greater than CN ([[125]I]IPPI = 1.3, [[125]I]IBETA = 1.2). A positive correlation between [[125]I]IPPI and [[125]I]IBETA binding suggests a synergistic relationship between tau and Aβ plaque in DSAD and AD pathology. This study demonstrates that [[125]I]IPPI and [[125]I]IBETA may serve as novel radiotracers in both DSAD and AD to continue diagnostic investigations.

To investigate the regulatory mechanism of BLACAT1 expression in sevoflurane (Sev)-induced neuronal cell injury. An in vitro model was created by treating microglial cell lines with 3% Sev. An in vivo model was created by administering 2.2% Sev gas inhalation to mice for three consecutive days. Learning and memory capacity was assessed using the Morris water maze test. Gene expression was detected via RT-qPCR, while cellular functional alterations were observed through CCK-8 assays and flow cytometry. ELISA monitored inflammatory cytokine levels, while assay kits assessed oxidative stress marker expression. Dual luciferase reporter assay and RNA immunoprecipitation validated gene-target relationships. Treatment with Sev increased BLACAT1 levels in microglia and mouse hippocampi, while reducing the expression of miR-361-3p. Transfection with si-BLACAT1 counteracted the inhibitory effects of Sev on cell proliferation while reducing inflammatory and oxidative stress levels. miR-361-3p was a downstream target of BLACAT1, with miR inhibitor counteracting si-BLACAT1's protective effects on damaged neurons. Furthermore, Sev treatment impaired learning and memory functions in the mouse hippocampus, as evidenced by prolonged escape latency and fewer platform crossings during the original platform phase. BLACAT1 participates in Sev-induced glial cell injury via miR-361-3p, leading to hippocampal cognitive dysfunction.