Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway.

Spatial learning and memory flexibility are known to require long-term potentiation (LTP) and long-term depression (LTD), respectively, on a cellular basis. We previously showed that cyclin Y (CCNY), a synapse-remodeling cyclin, is a novel actin-binding protein and an inhibitory regulator of functional and structural LTP in vitro. In this study, we report that Ccny knockout (KO) mice exhibit enhanced LTP and weak LTD at Schaffer collateral-CA1 synapses in the hippocampus. In accordance with enhanced LTP, Ccny KO mice showed improved spatial learning and memory. However, although previous studies reported that normal LTD is necessary for memory flexibility, Ccny KO mice intriguingly showed improved memory flexibility, suggesting that weak LTD could exert memory flexibility when combined with enhanced LTP. At the molecular level, CCNY modulated spatial learning and memory flexibility by distinctively affecting the cofilin-actin signaling pathway in the hippocampus. Specifically, CCNY inhibited cofilin activation by original learning, but reversed such inhibition by reversal learning. Furthermore, viral-mediated overexpression of a phosphomimetic cofilin-S3E in hippocampal CA1 regions enhanced LTP, weakened LTD, and improved spatial learning and memory flexibility, thus mirroring the phenotype of Ccny KO mice. In contrast, the overexpression of a non-phosphorylatable cofilin-S3A in hippocampal CA1 regions of Ccny KO mice reversed the synaptic plasticity, spatial learning, and memory flexibility phenotypes observed in Ccny KO mice. Altogether, our findings demonstrate that LTP and LTD cooperatively regulate memory flexibility. Moreover, CCNY suppresses LTP while facilitating LTD in the hippocampus and negatively regulates spatial learning and memory flexibility through the control of cofilin-actin signaling, proposing CCNY as a learning regulator modulating both memorizing and forgetting processes.

Investigating how individual differences influence responses to the COVID-19 crisis: The role of maladaptive and five-factor personality traits.

INTRODUCTION: Coronavirus disease (COVID-19) pandemic impacted both the physical and psychological aspects of people's lives. Personality traits are one of the factors that explain the diverse responses to stressful situations. This study aimed to investigate whether five-factor and maladaptive personality traits are associated with depressive and anxiety symptoms, suicide risk, self-reported COVID-19 symptoms, and preventive behaviors during the COVID-19 pandemic, comprehensively. METHODS: We conducted an online survey among a representative sample of 1000 Koreans between May 8 to 13, 2020. Participants' five-factor and maladaptive personality traits were measured using the multidimensional personality inventory, the Bright and Dark Personality Inventory. COVID-19 symptoms, depressive and anxiety symptoms, suicide risk, and preventive behaviors were also measured. RESULTS: The results revealed that maladaptive personality traits (e.g., negative affectivity, detachment) had positive correlations with depressive and anxiety symptoms, suicide risk, and COVID-19 symptoms, and the five-factor personality traits (e.g., agreeableness, conscientiousness) had positive correlations with preventive behaviors. CONCLUSION: Our findings extend the current understanding of the relationship between five-factor and maladaptive personality traits and responses to the COVID-19 pandemic. Longitudinal follow-up should further investigate the influence of personality traits on an individual's response to the COVID-19 pandemic.

Ccny knockout mice display an enhanced susceptibility to kainic acid-induced epilepsy.

Cyclin Y (CCNY) is a member of cyclin superfamily proteins involved in the regulation of the cell cycle in proliferating cells. Intriguingly, CCNY is highly expressed in terminally differentiated neuronal cells of multiple brain regions and acts as a postsynaptic protein, which plays an inhibitory role in long-term potentiation. However, the pathophysiological significance of CCNY in the nervous system remains largely unexplored. In this study, we revisited our RNA-sequencing (RNA-seq) data obtained from cultured hippocampal neurons virally overexpressing or depleting CCNY. Using RNA-seq-based bioinformatic disease analysis and synaptic gene ontology analysis, we identified that numerous genes associated with epilepsy (e.g. Chrna4, Gabrd, Nhlrc1, Reln, Samd12, Slc6a1, etc.) or neurodegenerative diseases (e.g. Psen1, Pdyn, Ndrg1, etc.) are affected by the level of CCNY expression. In agreement with the RNA-seq-based disease analysis, we found that Ccny knockout (KO) mice are more susceptible to kainic acid-induced epilepsy than wild-type mice. In addition, some epilepsy-associated genes that are regulated by CCNY levels were further validated in the brain of Ccny KO mice at the mRNA and protein levels. Collectively, our findings indicate that CCNY shifts the expression profile of epilepsy-associated genes and exerts a protective effect against kainic acid-induced epilepsy, suggesting CCNY as a potential pharmaceutical candidate for the treatment of epilepsy.

Palmitoylation in Alzheimer's disease and other neurodegenerative diseases.

Posttranslational modifications of proteins are important regulatory processes endowing the proteins functional complexity. Over the last decade, numerous studies have shed light on the roles of palmitoylation, one of the most common lipid modifications, in various aspects of neuronal functions. Major players regulating palmitoylation are the enzymes that mediate palmitoylation and depalmitoylation which are palmitoyl acyltransferases (PATs) and protein thioesterases, respectively. In this review, we will provide and discuss current understandings on palmitoyation/depalmitoylation control mediated by PATs and/or protein thioesterases for neuronal functions in general and also for Alzheimer's disease in particular, and other neurodegenerative diseases such as Huntington's disease, schizophrenia and intellectual disability.

Development and validation of the core life activities scale.

Life activities profoundly influence well-being, mental health, and quality of life. The COVID-19 pandemic has heightened the importance of monitoring these activities for psychological and emotional health. However, existing measurement tools are limited, particularly for assessing psychological health. To address this gap, we developed and validated the Core Life Activities (CORE) scale, comprising five key factors (sleep, exercise, learning, diet, and social relationships) identified in neuroscience, cognitive psychology, and gerontology. In Study 1 (n = 1,137), exploratory and confirmatory factor analyses supported a single-factor structure with good model fit (χ2 = 6.377, df = 3, TLI = 0.992, CFI = 0.998, RMSEA = 0.031), demonstrating robust internal consistency (Cronbach's alpha = 0.776) and test-retest reliability (intraclass correlation coefficient = 0.522, p < 0.001). The CORE exhibited significant convergent validity with mental health screening tools for depressive and anxiety disorders and suicidality. Study 2 (n = 684) confirmed a significant correlation between CORE and the World Health Organisation Quality of Life Brief Version, complementing the convergent validity found in Study 1. In addition, discriminant validity was confirmed by a non-significant correlation with the COVID-19 Preventive Behavior Scale. The findings establish the CORE as a reliable and valid tool, offering a simple yet comprehensive measure for assessing core life activities with potential applications in diverse environments.

14-3-3γ haploinsufficiency leads to altered dopamine pathway and Parkinson's disease-like motor incoordination in mice.

The 14-3-3 protein family with seven isoforms found in mammals is widely expressed in the brain and plays various roles in cellular processes. Several studies have reported that 14-3-3γ, one of the 14-3-3 protein isoforms, is associated with neurological and psychiatric disorders, but the role of 14-3-3γ in the pathophysiology of brain diseases is unclear. Although studies have been conducted on the relationship between 14-3-3γ protein and Parkinson's disease (PD), a common neurodegenerative disorder with severe motor symptoms such as bradykinesia and rigidity, a direct connection remains to be elucidated. We recently showed that adult heterozygous 14-3-3γ knockout mice are hyperactive and exhibit anxiety-like behavior. In this study, we further characterized the molecular and behavioral changes in aged 14-3-3γ heterozygous mice to investigate the role of 14-3-3γ in the brain. We observed decreased dopamine levels and altered dopamine metabolism in the brains of these mice, including changes in the phosphorylation of proteins implicated in PD pathology. Furthermore, we confirmed that they displayed PD symptom-like behavioral deficits, such as impaired motor coordination and decreased ability to the nest-building activity. These findings suggest an association between 14-3-3γ dysfunction and PD pathophysiology.

Neuroprotection by urokinase plasminogen activator in the hippocampus.

Tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), which are both used for thrombolytic treatment of acute ischemic stroke, are serine proteases that convert plasminogen to active plasmin. Although recent experimental evidences have raised controversy about the neurotoxic versus neuroprotective roles of tPA in acute brain injury, uPA remains unexplored in this context. In this study, we evaluated the effect of uPA on neuronal death in the hippocampus of mice after kainate-induced seizures. In the normal brain, uPA was localized to both nuclei and cytosol of neurons. Following severe kainate-induced seizures, uPA completely disappeared in degenerating neurons, whereas uPA-expressing astrocytes substantially increased, suggesting reactive astrogliosis. uPA-knockout mice were more vulnerable to kainate-induced neuronal death than wild-type mice. Consistent with this, inhibition of uPA by intracerebral injection of the uPA inhibitor UK122 increased the level of neuronal death. In contrast, prior administration of recombinant uPA significantly attenuated neuronal death. Collectively, these results indicate that uPA renders neurons resistant to kainate-induced excitotoxicity. Moreover, recombinant uPA suppressed cell death in primary cultures of hippocampal neurons exposed to H2O2, zinc, or various excitotoxins, suggesting that uPA protects against neuronal injuries mediated by the glutamate receptor, or by oxidation- or zinc-induced death signaling pathways. Considering that tPA may facilitate neurodegeneration in acute brain injury, we suggest that uPA, as a neuroprotectant, might be beneficial for the treatment of acute brain injuries such as ischemic stroke.

Cyclin Y, a novel actin-binding protein, regulates spine plasticity through the cofilin-actin pathway.

While positive regulators of hippocampal long-term potentiation (LTP) have extensively been investigated, relatively little is known about the inhibitory regulators of LTP. We previously reported that Cyclin Y (CCNY), a member of cyclin family generally known to function in proliferating cells, is a novel postsynaptic protein that serves as a negative regulator of functional LTP. However, whether CCNY plays a role in structural LTP, which is mechanistically linked to functional LTP, and which mechanisms are involved in the CCNY-mediated suppression of LTP at the molecular level remain elusive. Here, we report that CCNY negatively regulates the plasticity-induced changes in spine morphology through the control of actin dynamics. We observed that CCNY directly binds to filamentous actin and interferes with LTP-induced actin polymerization as well as depolymerization by blocking the activation of cofilin, an actin-depolymerizing factor, thus resulting in less plastic spines and the impairment of structural LTP. These data suggest that CCNY acts as an inhibitory regulator for both structural and functional LTP by modulating actin dynamics through the cofilin-actin pathway. Collectively, our findings provide a mechanistic insight into the inhibitory modulation of hippocampal LTP by CCNY, highlighting a novel function of a cyclin family protein in non-proliferating neuronal cells.

Apolipoprotein E ablation decreases synaptic vesicular zinc in the brain.

Both apolipoprotein E (apoE) and zinc are involved in amyloid ß (Aß) aggregation and deposition, in the hallmark neuropathology of Alzheimer's disease (AD). Recent studies have suggested that interaction of apoE with metal ions may accelerate amyloidogenesis in the brain. Here we examined the impact of apoE deficiency on the histochemically reactive zinc pool in the brains of apoE knockout mice. While there was no change in total contents of metals (zinc, copper, and iron), the level of histochemically reactive zinc (principally synaptic zinc) was significantly reduced in the apoE-deficient brain compared to wild-type. This reduction was accompanied by reduced expressions of the presynaptic zinc transporter, ZnT3, as well as of the δ-subunit of the adaptor protein complex-3 (AP3δ), which is responsible for post-translational stability and activity of ZnT3. In addition, the level of histochemically reactive zinc was also decreased in the cerebrovascular micro-vessels of apoE-deficient mice, the site of cerebral amyloid angiopathy in AD. These results suggest that apoE may affect the cerebral free zinc pool that contributes to AD pathology.

Emerging roles of 14-3-3γ in the brain disorder.

14-3-3 proteins are mostly expressed in the brain and are closely involved in numerous brain functions and various brain disorders. Among the isotypes of the 14-3-3 proteins, 14-3-3γ is mainly expressed in neurons and is highly produced during brain development, which could indicate that it has a significance in neural development. Furthermore, the distinctive levels of temporally and locally regulated 14-3-3γ expression in various brain disorders suggest that it could play a substantial role in brain plasticity of the diseased states. In this review, we introduce the various brain disorders reported to be involved with 14-3-3γ, and summarize the changes of 14-3-3γ expression in each brain disease. We also discuss the potential of 14-3-3γ for treatment and the importance of research on specific 14-3-3 isotypes for an effective therapeutic approach. [BMB Reports 2020; 53(10): 500-511].

Upregulation of tPA/plasminogen proteolytic system in the periphery of amyloid deposits in the Tg2576 mouse model of Alzheimer's disease.

Although the tissue plasminogen activator (tPA)/plasminogen/plasmin proteolytic system is thought to modulate the catabolism of amyloid-beta (Abeta), in vivo evidence remains insufficient. In the brain of human amyloid precursor protein transgenic Tg2576 mice, we found co-accumulation of tPA and plasminogen at the periphery of compact amyloid deposits, mainly Abeta42-cored plaques, as well as in the walls of blood vessels with cerebral amyloid angiopathy (CAA). This tPA/plasminogen system contained high levels of proteolytic activity. High levels of tPA were also found in reactive astrocytes with increased Abeta42 expression, whereas plasminogen was found only in neurons. When the brain sections of Tg2576 mice were treated with both tPA and plasminogen, levels of thioflavin-S fluorescence, congophilicity and birefringence in the compact amyloid plaques were significantly reduced, and the ultrastructure of Abeta42-fibrils was disrupted. These results suggest that the assembled Abeta42 may promote upregulation of the tPA/plasminogen proteolytic system, which can modulate the deposition of amyloid plaques in vivo.

Dorsal and Ventral Hippocampus Differentiate in Functional Pathways and Differentially Associate with Neurological Disease-Related Genes during Postnatal Development.

The dorsal and ventral regions of the hippocampus are important in cognitive and emotional processing, respectively. Various approaches have revealed the differential molecular and structural characteristics, and functional roles of the hippocampus. Recent RNA sequencing (RNA-seq) technology has enriched our understanding of the hippocampus by elucidating more detailed information on gene expression patterns. However, no RNA-seq-based study on gene profiles in the developing hippocampus has been reported. Using RNA-seq-based bioinformatic analysis in conjunction with quantitative real-time polymerase chain reaction analysis and a comparison of in situ hybridization data obtained from the Allen Brain Atlas, we provide a thorough analysis of differentially expressed genes in the dorsal and ventral hippocampus at specific developmental ages representing the postnatally maturing hippocampus. Genes associated with particular functional pathways and marker genes for particular neurological diseases were found to be distinctively segregated within either the dorsal or ventral hippocampus at specific or at all developmental ages examined. We also report novel molecular markers enriched in the dorsal or ventral hippocampus. Taken together, this study provides insights into the molecular mechanisms underlying physiological functions linked to the dorsal or ventral hippocampus. The information provided in the study also contributes to a better understanding of brain functions and serves as a resource for future studies on the pathophysiology of dorsal and ventral hippocampal functions.

Cyclin Y inhibits plasticity-induced AMPA receptor exocytosis and LTP.

Cyclin Y (CCNY) is a member of the cyclin protein family, known to regulate cell division in proliferating cells. Interestingly, CCNY is expressed in neurons that do not undergo cell division. Here, we report that CCNY negatively regulates long-term potentiation (LTP) of synaptic strength through inhibition of AMPA receptor trafficking. CCNY is enriched in postsynaptic fractions from rat forebrain and is localized adjacent to postsynaptic sites in dendritic spines in rat hippocampal neurons. Using live-cell imaging of a pH-sensitive AMPA receptor, we found that during LTP-inducing stimulation, CCNY inhibits AMPA receptor exocytosis in dendritic spines. Furthermore, CCNY abolishes LTP in hippocampal slices. Taken together, our findings demonstrate that CCNY inhibits plasticity-induced AMPA receptor delivery to synapses and thereby blocks LTP, identifying a novel function for CCNY in post-mitotic cells.

Alteration of the cerebral zinc pool in a mouse model of Alzheimer disease.

Synaptic vesicle Zn is regulated by zinc transporter 3 (ZnT3) and is involved in neurotransmission and synaptic plasticity. Here, we describe extensive alterations of ZnT3-regulated Zn pools in the brains of human amyloid precursor protein-transgenic (Tg2576) mice. In contrast to wild-type littermates in which ZnT3 expression and synaptic Zn increased with age, there were age-dependent reductions in ZnT3 expression and synaptic Zn levels in the hippocampal mossy fiber area of Tg2576 mice. In these mice, a novel Zn pool and ZnT3 expression were colocalized and appeared along dystrophic neurites surrounding compact amyloid plaques that were identified by in situ blue fluorescence, congophilic birefringence, and Aß42 immunoreactivity. Zn-specific histofluorescence and ZnT3 immunofluorescence in dystrophic neurites were also colocalized with the δ-subunit of adaptor protein complex 3, lysosome-associated membrane protein, cathepsin D, and neurofilament-containing hyperphosphorylated paired helical filaments. The synaptic vesicle marker protein synaptophysin and vesicle-associated membrane protein were not found in these neurites, suggesting a role of ZnT3 distinct from itsnormal role in synaptic Zn. ZnT3 immunoreactivity and Zn histofluorescence were also evident in activated astrocytes. These datasuggest that extensive modifications of the cerebral Zn pool, particularly synaptic Zn, may underlie neuronal dysfunction characteristic of Alzheimer disease.

Ibudilast, a phosphodiesterase inhibitor with anti-inflammatory activity, protects against ischemic brain injury in rats.

Ibudilast, a non-selective phosphodiesterase inhibitor, is clinically used in patients with stroke or dizziness. However, whether the compound exerts a beneficial effect on acute ischemic stroke remains to be established. We used a rat model of transient focal cerebral ischemia using middle cerebral artery occlusion (MCAO) and reperfusion, and explored the effects of ibudilast on infarction size, brain edema, atrophy, and nerve cell death. Neurological outcomes (behavior and mortality) of rats were also assessed. An intravenous administration of ibudilast attenuated the size of cerebral infarction in a dose-dependent manner, with the most significant reduction achieved at the dose of 10mg/kg. Ibudilast induced a significant reduction in infarct size when administered 30min before MCAO or 0-2h after reperfusion, with the largest reduction observed at 30min before MCAO and 1h after reperfusion. Ibudilast significantly attenuated brain edema formation, cerebral atrophy and apoptosis of nerve cells preferentially in the cortical penumbra area, and also significantly reduced mortality and improved neurological outcomes. Expression of various inflammatory mediator molecules in both hemispheres was markedly suppressed by ibudilast. We conclude that ibudilast exerts beneficial effects against acute brain ischemia in an animal model.

Endogenous zinc mediates apoptotic programmed cell death in the developing brain.

Endogenous zinc can mediate the apoptotic programmed cell death (PCD) in the developing brain. Intensive accumulation of labile zinc occurs in almost all neurons undergoing PCD in the developing rat brain. Based on the greater frequency of neurons with intensive zinc accumulation compared to apoptotic neurons, it is inferred that cytosolic zinc accumulation precedes apoptotic PCD. To determine the role of intracellular labile zinc in developmental apoptosis, we subcutaneously injected the membrane-permeant zinc chelator, N,N,N',N-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) into postnatal rats for 7 days after birth. TPEN chelated intraneuronal zinc without modulating the expression of the zinc-regulating proteins, ZnT-1, ZnT-3, and synaptophysin. The frequency of apoptotic neurons significantly decreased in TPEN-treated rat brains compared with that in normal postnatal rats. Activating cleavages of caspase-9 and -3, and mitochondrial pro-apoptotic Bax expression were reduced, whereas expression of anti-apoptotic Bcl-2 was increased. Thus, intracerebral zinc chelation may arrest PCD in the developing brain by interfering with the caspase-dependent apoptotic pathway. The present study demonstrates that intracellular zinc acts as a key mediator of developmental apoptosis and therefore provides the first in vivo evidence that endogenous labile zinc causes neuronal apoptosis.

Cytosolic labile zinc accumulation in degenerating dopaminergic neurons of mouse brain after MPTP treatment.

High levels of labile zinc accumulate in degenerating neurons after brain injury, such as ischemic stroke, trauma, epilepsy, and hypoglycemia. Cytosolic zinc accumulation is also found in brain neurons undergoing apoptosis during development or after neuronal target ablation. Thus, staining with zinc-specific probes can be used to identify neuronal death in the brain. In this study, mice were intraperitoneally given four 20 mg/kg doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 2-hour intervals, and dopaminergic neurons were then evaluated for zinc accumulation and apoptosis. In the substantia nigra pars compacta, zinc-specific fluorescent dyes revealed that all degenerating neurons, identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), or acid fuchsin or Fluoro-Jade C staining, contained high levels of cytosolic labile zinc. Nuclear condensation/fragmentation was noted in dopaminergic neurons with cytosolic zinc accumulation, indicating apoptotic cell death. These findings support the supposition that cytosolic labile zinc accumulation is an indicator of degenerating dopaminergic neurons in animal models of Parkinson's disease.