Rapid and local neuroestrogen synthesis supports long-term potentiation of hippocampal Schaffer collaterals-cornu ammonis 1 synapse in ovariectomized mice.

In aging women, cognitive decline and increased risk of dementia have been associated with the cessation of ovarian hormones production at menopause. In the brain, presence of the key enzyme aromatase required for the synthesis of 17-ß-estradiol (E2) allows for local production of E2 in absence of functional ovaries. Understanding how aromatase activity is regulated could help alleviate the cognitive symptoms. In female rodents, genetic or pharmacological reduction of aromatase activity over extended periods of time impair memory formation, decreases spine density, and hinders long-term potentiation (LTP) in the hippocampus. Conversely, increased excitatory neurotransmission resulting in rapid N-methyl-d-aspartic acid (NMDA) receptor activation rapidly promotes neuroestrogen synthesis. This rapid modulation of aromatase activity led us to address the hypothesis that acute neuroestrogens synthesis is necessary for LTP at the Schaffer collateral-cornu ammonis 1 (CA1) synapse in absence of circulating ovarian estrogens. To test this hypothesis, we did electrophysiological recordings of field excitatory postsynaptic potential (fEPSPs) in hippocampal slices obtained from ovariectomized mice. To assess the impact of neuroestrogens synthesis on LTP, we applied the specific aromatase inhibitor, letrozole, before the induction of LTP with a theta burst stimulation protocol. We found that blocking aromatase activity prevented LTP. Interestingly, exogenous E2 application, while blocking aromatase activity, was not sufficient to recover LTP in our model. Our results indicate the critical importance of rapid, activity-dependent local neuroestrogens synthesis, independent of circulating hormones for hippocampal synaptic plasticity in female rodents.

Unlocking choline's potential in Alzheimer's disease: A narrative review exploring the neuroprotective and neurotrophic role of phosphatidylcholine and assessing its impact on memory and learning.

BACKGROUND AND AIMS: Growing evidence suggests nutritional intervention may influence the development and progression of Alzheimer's Disease (AD). Choline, an essential dietary nutrient plays a critical role in neurological development and brain function, however, its effects on AD in humans is unclear. The research aims to investigate mechanistic links between dietary choline intake and cognitive functioning, focusing on the role of phosphatidylcholine (PC) in neuroplasticity and its interaction with amyloid beta (Aß) peptides in neuron membranes. Additionally, human evidence on the potential benefits of PC interventions on AD, cognition, and proposed mechanisms are evaluated. METHODS: A reproducible systematic literature search was performed using a three-tranche strategy, consisting of a review, mechanism, and intervention search. Using PubMed as the main database, 1254 titles and abstracts were screened, 149 papers were read in full and 65 peer-reviewed papers were accepted, critically appraised, and analysed in a narrative review. RESULTS: Predominantly preclinical evidence demonstrated that PC enhances neuroplasticity, a key biological substrate for cognition, by activating intracellular neuronal signalling pathways or through neuron membrane function. Molecular dynamic simulation methods provided a mechanistic understanding of the interconnection between neuronal PC content and the potential behaviour and trajectory of Aß peptide aggregation. The results indicate that the neuronal membrane composition of PC is critical to inhibiting Aß aggregation and neuronal damage, protecting the neuron from Aß toxicity. This might provide a foundation for optimising cellular PC which may prove beneficial in the treatment or prevention of neurodegenerative disease. Altered PC metabolism in AD was evidenced in observational studies; however, whether this relationship represents a cause or consequence of AD remains to be determined. Human intervention studies did not produce conclusive evidence supporting its effectiveness in enhancing cognitive function. This lack of consistency primarily stems from methodological constraints within the conducted studies. Human observational research provided the most compelling evidence linking a higher dietary PC intake to a reduced risk of dementia and significant improvements in cognitive testing. CONCLUSION: Despite the lack of randomised control trials (RCTs) assessing the efficacy of lecithin/PC to improve cognition in AD patients, there exists promising evidence supporting its neuroprotective and neurotrophic role. This review establishes an evidence-based framework through chains of mechanistic evidence, that may provide potential strategies for enhanced neuroprotection and reduced neurodegeneration caused by AD. Considering the escalating global burden of AD and the current shortcomings in effective treatments, this review together with the limitations and gaps identified in the existing research presents valuable insights that emphasise the urgency of more comprehensive research into the relationship between PC and AD.

Melatonin attenuates intermittent hypoxia-induced cognitive impairment in aged mice: The role of inflammation and synaptic plasticity.

Intermittent hypoxia (IH), a major pathophysiologic alteration in obstructive sleep apnea syndrome (OSAS), is an important contributor to cognitive impairment. Increasing research suggests that melatonin has anti-inflammatory properties and improves functions related to synaptic plasticity. However, it is unclear whether melatonin has a protective effect against OSAS-induced cognitive dysfunction in aged individuals and the involved mechanisms are also unclear. Therefore, in the study, the effects of exposure to IH alone and IH in combination with daily melatonin treatment were investigated in C57BL/6 J mice aged 18 months. Assessment of the cognitive ability of mice in a Morris water maze showed that melatonin attenuated IH-induced impairment of learning and memory in aged mice. Enzyme-linked immunosorbent assay, polymerase chain reaction, and western blotting molecular techniques showed that melatonin treatment reduced the levels of the proinflammatory cytokines, interleukin-1ß, interleukin-6, and tumor necrosis factor-α, decreased the levels of NOD-like receptor thermal protein domain associated protein 3 and nuclear factor kappa-B, lowered the levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and increased the levels of the synaptic proteins, activity-regulated cytoskeleton-associated protein, growth-associated protein-43, postsynaptic density protein 95, and synaptophysin in IH-exposed mice. Moreover, electrophysiological results showed that melatonin ameliorated the decline in long-term potentiation induced by IH. The results suggest that melatonin can ameliorate IH-induced cognitive deficits by inhibiting neuroinflammation and improving synaptic plasticity in aged mice.

The synaptic vesicle cluster as a controller of pre- and postsynaptic structure and function.

The synaptic vesicle cluster (SVC) is an essential component of chemical synapses, which provides neurotransmitter-loaded vesicles during synaptic activity, at the same time as also controlling the local concentrations of numerous exo- and endocytosis cofactors. In addition, the SVC hosts molecules that participate in other aspects of synaptic function, from cytoskeletal components to adhesion proteins, and affects the location and function of organelles such as mitochondria and the endoplasmic reticulum. We argue here that these features extend the functional involvement of the SVC in synapse formation, signalling and plasticity, as well as synapse stabilization and metabolism. We also propose that changes in the size of the SVC coalesce with changes in the postsynaptic compartment, supporting the interplay between pre- and postsynaptic dynamics. Thereby, the SVC could be seen as an 'all-in-one' regulator of synaptic structure and function, which should be investigated in more detail, to reveal molecular mechanisms that control synaptic function and heterogeneity.

A Nanobody-Based Proximity Ligation Assay Detects Constitutive and Stimulus-Regulated Native Arc/Arg3.1 Oligomers in Hippocampal Neuronal Dendrites.

Activity-regulated cytoskeleton-associated protein (Arc), the product of an immediate early gene, plays critical roles in synaptic plasticity and memory. Evidence suggests that Arc function is determined by its oligomeric state; however, methods for localization of native Arc oligomers are lacking. Here, we developed a nanobody-based proximity ligation assay (PLA) for detection, localization, and quantification of Arc-Arc complexes in primary rat hippocampal neuronal cultures. We used nanobodies with single, structurally defined epitopes in the bilobar Arc capsid domain. Nanobody H11 binds inside the N-lobe ligand pocket, while nanobody C11 binds to the C-lobe surface. For each nanobody, ALFA- and FLAG-epitope tags created a platform for antibody binding and PLA. Surprisingly, PLA puncta in neuronal dendrites revealed widespread constitutive Arc-Arc complexes. Treatment of cultures with tetrodotoxin or cycloheximide had no effect, suggesting stable complexes that are independent of recent neuronal activity and protein synthesis. To assess detection of oligomers, cultures were exposed to a cell-penetrating peptide inhibitor of the Arc oligomerization motif (OligoOFF). Arc-Arc complexes detected by H11 PLA were inhibited by OligoOff but not by control peptide. Notably, Arc complexes detected by C11 were unaffected by OligoOFF. Furthermore, we evaluated Arc complex formation after chemical stimuli that increase Arc synthesis. Brain-derived neurotrophic factor increased Arc-Arc signal detected by C11, but not H11. Conversely, dihydroxyphenylglycine (DHPG) treatment selectively enhanced H11 PLA signals. In sum, nanobody-based PLA reveals constitutive and stimulus-regulated Arc oligomers in hippocampal neuronal dendrites. A model is proposed based on detection of Arc dimer by C11 and higher-order oligomer by H11 nanobody.

Postsynaptic Density Proteins and Their Role in the Trafficking of Group I Metabotropic Glutamate Receptors.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system that regulates multiple different forms of synaptic plasticity, including learning and memory. Glutamate transduces its signal by activating ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). Group I mGluRs belong to the G protein-coupled receptor (GPCR) family. Regulation of cell surface expression and trafficking of the glutamate receptors represents an important mechanism that assures proper transmission of information at the synapses. There is growing evidence implicating dysregulated glutamate receptor trafficking in the pathophysiology of several neuropsychiatric disorders. The postsynaptic density (PSD) region consists of many specialized proteins which are assembled beneath the postsynaptic membrane of dendritic spines. Many of these proteins interact with group I mGluRs and have essential roles in group I mGluR-mediated synaptic function and plasticity. This review provides up-to-date information on the molecular determinants regulating cell surface expression and trafficking of group I mGluRs and discusses the role of few of these PSD proteins in these processes. As substantial evidences link mGluR dysfunction and maladaptive functioning of many PSD proteins to the pathophysiology of various neuropsychiatric disorders, understanding the role of the PSD proteins in group I mGluR trafficking may provide opportunities for the development of novel therapeutics in multiple neuropsychiatric disorders.

Stress molecular signaling in interaction with cognition.

Exposure to stressful life events is associated with a high risk of developing psychiatric disorders with a wide variety of symptoms. Cognitive symptoms in stress-related psychiatric disorders can be particularly challenging to understand, both for those experiencing them and for healthcare providers. To gain insights, it is important to capture stress-induced structural, epigenomic, transcriptomic, and proteomic changes in relevant brain regions such as the amygdala, hippocampus, locus coeruleus and prefrontal cortex, resulting in long-lasting alterations in brain function. In this review, we will emphasize a subset of stress molecular mechanisms altering neuroplasticity, neurogenesis, and balance between excitatory and inhibitory neurons. We then discuss how to identify genetic risk factors that may accelerate stress-driven or stress-induced cognitive impairment. Despite the development of new technologies such as single-cell resolution sequencing, our understanding of the molecular effects of stress in the brain remains to be deepened. A better understanding of the diversity of stress effects in different brain regions and cell types is a pre-requisite to open new avenues for mechanism-informed prevention and treatment of stress-related cognitive symptoms.

From blood to brain: Exploring the role of fibrinogen in the pathophysiology of depression and other neurological disorders.

Recent findings indicate that fibrinogen, a protein involved in blood clotting, plays a significant role in neuroinflammation and mood disorders. Elevated fibrinogen levels are consistently observed in individuals with depression, potentially contributing to microglial activation. This could impair fibrinolysis and contribute to a pro-inflammatory environment in the brain. This neuroinflammatory response can impair neuroplasticity, a key process for learning, memory, and mood regulation. Fibrinogen may also indirectly influence neurotransmitters like serotonin, which play a vital role in mood regulation. Furthermore, fibrinogen's interaction with astrocytes may trigger a cascade of events leading to demyelination, a process where the protective sheath around nerve fibers deteriorates. This can disrupt communication within the nervous system and contribute to depression symptoms. Intriguingly, targeting fibrinogen or related pathways holds promise for therapeutic interventions. For instance, modulating PAI-1 (Plasminogen activator inhibitor-1) activity or inhibiting fibrinogen's interaction with brain cells could be potential strategies. This review explores the multifaceted relationship between fibrinogen and neurological disorders with a focus on depression highlighting its potential as a therapeutic target. Further research is necessary to fully elucidate the mechanisms underlying this association and develop effective therapeutic strategies targeting the fibrinolytic system for mood disorders.

Astrocytes contribute to the functional differentiation of the hippocampal longitudinal axis during reward and aversion processing in the adult male rat.

This study aims to investigate whether glial cells, in particular putative astrocytes, contribute to functional distinctions between the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus. To evaluate this, we performed three different behavioral tasks (i.e., Morris water maze; MWM, Passive avoidance; PA, T-maze place preference; TPP) to determine whether the DH, IH, and VH are necessary for each task. Sensitivity of behavioral tasks was confirmed using lidocaine (2 %, 1 µl) reversible inactivation. Subsequently, we examined the effects of silencing astrocytes, using fluorocitrate (FC, 1 mM/1 µl), into the DH, IH, and VH on these tasks. The effects of drugs were examined separately. We observed that injection of FC into the DH resulted in a significant impairment in MWM performance. In contrast, while FC injections into the IH or VH did not prevent platform localization during the acquisition phase, rats showed difficulty recalling the target zone during the retrieval phase. In the PA test, FC injection into the VH impaired task learning and memory. During the acquisition phase, FC injection into the DH or IH did not differ from the control in the number of shocks; however, during retrieval, there was a significant decrease in the latency before entering the dark chamber. The TPP test performance was impaired by FC injection in the IH. In sum, we show that glial cells, especially astrocytes in specific functional regions of the hippocampus, play distinct roles in processing aversive and rewarding experiences and contribute to the functional organization of the hippocampal longitudinal axis.

Role of SIRT1-mediated synaptic plasticity and neurogenesis: Sex-differences in antidepressant-like efficacy of catalpol.

BACKGROUND: Catalpol, an important compound found in Rehmannia glutinosa (a plant with high nutritional and antidepressant medicinal value), exhibits various biological activities and has the ability to penetrate the blood-brain barrier. Our recent studies revealed a gender difference in the antidepressant activity of Rehmannia glutinosa with females showing better responses than males. Catalpol is likely the key compound responsible for this gender-specific difference, which caters to current clinical observations that the severity and impact of depression are approximately two to three times higher in females than in males. However, the sex-specific mechanism of catalpol's antidepressant effects remains unclear. PURPOSE AND METHODS: Our recent molecular network predictions suggest that the gender-specific antidepressant properties of catalpol primarily involve the regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Building on this, the present study used a well-established chronic unpredictable mild stress model of depression in mice to confirm the sex-specific antidepressant characteristics of catalpol over time and intensity. Furthermore, using SIRT1 inhibitors and activators, behavioral tests, hematoxylin & eosin, Nissl, and Golgi staining, western blotting, immunofluorescence, and real-time PCR, we evaluated the key indicators of depressive behavior, synaptic plasticity, and neurogenesis before and after SIRT1 intervention to comprehensively assess whether the sex-specific antidepressant mechanism of catalpol indeed involves SIRT1-mediated synaptic plasticity and neurogenesis. RESULTS: The gender-dependent antidepressant effects of catalpol are characterized by a faster onset and stronger effects in females compared to males, with females showing stronger regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Activation of SIRT1 preserved the gender differences in catalpol's effects on depressive behavior, hippocampal synaptic plasticity (including neuronal consolidation, neuronal density, dendritic spines, and PSD95 and SYP gene and protein expression), and neurogenesis (including enhancement of GAP43 and MAP2 expression, activation of c-myc, cyclinD1, Ngn2, and NeuroD1 mRNA levels, and upregulation of the Wnt3a/ß-catenin/GSK-3ß pathway), while inhibition of SIRT1 abolished these gender differences in the effects of catalpol. CONCLUSIONS: Catalpol exhibits higher antidepressant activity in female mice compared to male mice, and the mechanism underlying this gender difference in antidepressant effects may depend on catalpol's higher sensitivity in improving hippocampal SIRT1-mediated synaptic plasticity and neurogenesis in females. The novelty of this study lies in its first-time revelation of the gender-specific phenotypes, targets, and molecular mechanisms of the antidepressant effects of catalpol.

Corrigendum: Traumatic stress produces delayed alterations of synaptic plasticity in basolateral amygdala.

[This corrects the article DOI: 10.3389/fpsyg.2019.02394.].

Ketamine and α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Receptor Potentiation in the Somatosensory Cortex: A Comprehensive Review.

Ketamine, a dissociative anesthetic primarily recognized for its antagonism of N-methyl-D-aspartate (NMDA) receptors, has gained significant attention for its rapid antidepressant effects and potential in treating mood disorders. However, recent research indicates that ketamine's influence extends beyond NMDA receptor inhibition, affecting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and sensory processing. This review delves into ketamine's role in enhancing AMPA receptor function and its implications for sensory processing within the somatosensory cortex. AMPA receptors, essential for fast excitatory neurotransmission and synaptic plasticity, play a key role in sensory perception and integration. By examining preclinical and clinical studies, this review sheds light on how ketamine's modulation of AMPA receptors may improve sensory processing and contribute to its therapeutic effects. Additionally, the review explores the potential for ketamine-based therapies to treat sensory processing disorders and refine current treatment strategies. A deeper understanding of ketamine's complex effects on AMPA receptors and sensory processing could provide valuable insights for developing targeted interventions and advancing clinical applications.

Cofilin linked to GluN2B subunits of NMDA receptors is required for behavioral sensitization by changing the dendritic spines of neurons in the caudate and putamen after repeated nicotine exposure.

BACKGROUND: Nicotine dependence is associated with glutamatergic neurotransmission in the caudate and putamen (CPu) of the forebrain which includes alterations in the structure of dendritic spines at glutamate synapses. These changes after nicotine exposure can lead to the development of habitual behaviors such as smoking. The present study investigated the hypothesis that cofilin, an actin-binding protein that is linked to the GluN2B subunits of N-methyl-D-aspartate (NMDA) receptors regulates the morphology of dendritic spines in the neurons of the CPu after repeated exposure to nicotine. RESULTS: Adult male rats received subcutaneous injections of nicotine (0.3 mg/kg/day) or vehicle for seven consecutive days. DiI staining was conducted to observe changes in dendritic spine morphology. Repeated subcutaneous injections of nicotine decreased the phosphorylation of cofilin while increasing the formation of thin spines and filopodia in the dendrites of medium spiny neurons (MSN) in the CPu of rats. Bilateral intra-CPu infusion of the cofilin inhibitor, cytochalasin D (12.5 µg/µL/side), restored the thin spines and filopodia from mushroom types after repeated exposure to nicotine. Similar results were obtained from the bilateral intra-CPu infusion of the selective GluN2B subunit antagonist, Ro 25-6981 (4 µM/µL/side). Bilateral intra-CPu infusion of cytochalasin D that interferes with the actin-cofilin interaction attenuated the repeated nicotine-induced increase in locomotor sensitization in rats. CONCLUSIONS: These findings suggest that active cofilin alters the structure of spine heads from mushroom to thin spine/filopodia by potentiating actin turnover, contributing to behavioral sensitization after nicotine exposure.

Treadmill Exercise Facilitates Synaptic Plasticity in APP/PS1 Mice by Regulating Hippocampal AMPAR Activity.

Accumulating evidence underscores exercise as a straightforward and cost-effective lifestyle intervention capable of mitigating the risk and slowing the emergence and progression of Alzheimer's disease (AD). However, the intricate cellular and molecular mechanisms mediating these exercise-induced benefits in AD remain elusive. The present study delved into the impact of treadmill exercise on memory retrieval performance, hippocampal synaptic plasticity, synaptic morphology, and the expression and activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPARs) in 6-month-old APP/PS1 mice. APP/PS1 mice (4-month-old males) were randomly assigned to either a treadmill exercise group or a sedentary group, with C57BL/6J mice (4-month-old males) as the control group (both exercise and sedentary). The exercise regimen spanned 8 weeks. Our findings revealed that 8-week treadmill exercise reversed memory retrieval impairment in step-down fear conditioning in 6-month-old APP/PS1 mice. Additionally, treadmill exercise enhanced basic synaptic strength, short-term potentiation (STP), and long-term potentiation (LTP) of the hippocampus in these mice. Moreover, treadmill exercise correlated with an augmentation in synapse numbers, refinement of synaptic structures, and heightened expression and activity of AMPARs. Our findings suggest that treadmill exercise improves behavioral performance and facilitates synaptic transmission by increasing structural synaptic plasticity and the activity of AMPARs in the hippocampus of 6-month-old APP/PS1 mice, which is involved in pre- and postsynaptic processes.

Endocrine disrupting effects on morphological synaptic plasticity.

Neural regulation of the homeostasis depends on healthy synaptic function. Adaptation of synaptic functions to physiological needs manifests in various forms of synaptic plasticity (SP), regulated by the normal hormonal regulatory circuits. During the past several decades, the hormonal regulation of animal and human organisms have become targets of thousands of chemicals that have the potential to act as agonists or antagonists of the endogenous hormones. As the action mechanism of these endocrine disrupting chemicals (EDCs) came into the focus of research, a growing number of studies suggest that one of the regulatory avenues of hormones, the morphological form of SP, may well be a neural mechanism affected by EDCs. The present review discusses known and potential effects of some of the best known EDCs on morphological synaptic plasticity (MSP). We highlight molecular mechanisms altered by EDCs and indicate the growing need for more research in this area of neuroendocrinology.

The Orbitofrontal Cortex to Striatal Cholinergic Interneuron Circuit Controls Cognitive Flexibility Shaping Alcohol-Seeking Behavior.

BACKGROUND: A top-down neuronal circuit from the orbitofrontal cortex (OFC) to the dorsomedial striatum (DMS) appears to be critical for cognitive flexibility. However, how OFC projections to different types of neurons in the DMS control cognitive flexibility and contribute to substance seeking and use, which are relatively inflexible behaviors, remains unclear. METHODS: Mice were trained on two-bottle choice and operant alcohol self-administration procedures. The cognitive flexibility of the mice was tested through a place discrimination task. Electrophysiology and in vivo optogenetics were used to test the function of neural circuits in alcohol-seeking behavior. RESULTS: We depicted a connection from the OFC to striatal neurons and found that OFC afferents could elicit functional flexibility in striatal cholinergic interneurons (CINs). A mouse model of chronic alcohol consumption showed impaired cognitive flexibility and reduced burst-pause firing. The impairment of the OFC-DMS circuit resulted in a reduction in glutamatergic transmission in OFC-medium spiny neurons (MSNs) through a CIN-mediated pre-inhibition mechanism. Importantly, remodeling the OFC-DMS circuit by inducing LTP restored cognitive flexibility. Furthermore, CINs were responsible for the impact of remodeling of the OFC-DMS circuit on cognitive flexibility. This regulatory role of CINs preferentially facilitated the potentiation of glutamatergic transmission in D2 receptor-expressing medium spiny neurons (D2-MSNs) but not in D1-MSNs. Finally, activation of the OFC-CIN-D2-MSN circuit decreased alcohol-seeking behavior. CONCLUSIONS: Improving OFC-CIN circuit-mediated cognitive flexibility may provide a novel strategy for treating uncontrolled alcohol-seeking behavior.

Memory-efficient neurons and synapses for spike-timing-dependent-plasticity in large-scale spiking networks.

This paper addresses the challenges posed by frequent memory access during simulations of large-scale spiking neural networks involving synaptic plasticity. We focus on the memory accesses performed during a common synaptic plasticity rule since this can be a significant factor limiting the efficiency of the simulations. We propose neuron models that are represented by only three state variables, which are engineered to enforce the appropriate neuronal dynamics. Additionally, memory retrieval is executed solely by fetching postsynaptic variables, promoting a contiguous memory storage and leveraging the capabilities of burst mode operations to reduce the overhead associated with each access. Different plasticity rules could be implemented despite the adopted simplifications, each leading to a distinct synaptic weight distribution (i.e., unimodal and bimodal). Moreover, our method requires fewer average memory accesses compared to a naive approach. We argue that the strategy described can speed up memory transactions and reduce latencies while maintaining a small memory footprint.

Insight into brain metallothioneins from bidirectional Zn2+ signaling in synaptic dynamics.

The basal levels as the labile Zn2+ pools in the extracellular and intracellular compartments are in the range of ∼10 nM and ∼100 pM, respectively. The influx of extracellular Zn2+ is used for memory via cognitive activity and is regulated for synaptic plasticity, a cellular mechanism of memory. When Zn2+ influx into neurons excessively occurs, however, it becomes a critical trigger for cognitive decline and neurodegeneration, resulting in acute and chronic pathogenesis. Aging, a biological process, generally accelerates vulnerability to neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). The basal level of extracellular Zn2+ is age relatedly increased in the rat hippocampus, and the influx of extracellular Zn2+ contributes to accelerating vulnerability to the AD and PD pathogenesis in experimental animals with aging. Metallothioneins (MTs) are Zn2+-binding proteins for cellular Zn2+ homeostasis and involved in not only supplying functional Zn2+ required for cognitive activity, but also capturing excess (toxic) Zn2+ involved in cognitive decline and neurodegeneration. Therefore, it is estimated that regulation of MT synthesis is involved in both neuronal activity and neuroprotection. The present report provides recent knowledge regarding the protective/preventive potential of MT synthesis against not only normal aging but also the AD and PD pathogenesis in experimental animals, focused on MT function in bidirectional Zn2+ signaling in synaptic dynamics.

The effect of traumatic brain injury on learning and memory: A synaptic focus.

Deficits in learning and memory are some of the most commonly reported symptoms following a traumatic brain injury (TBI). We will examine whether the neural basis of these deficits stems from alterations to bidirectional synaptic plasticity within the hippocampus. Although the CA1 subregion of the hippocampus has been a focus of TBI research, the dentate gyrus should also be given attention as it exhibits a unique ability for adult neurogenesis, a process highly susceptible to TBI-induced damage. This review examines our current understanding of how TBI results in deficits in synaptic plasticity, as well as how TBI-induced changes in endocannabinoid (eCB) systems may drive these changes. Through the synthesis and amalgamation of existing data, we propose a possible mechanism for eCB-mediated recovery in synaptic plasticity deficits. This hypothesis is based on the plausible roles of CB1 receptors in regulating inhibitory tone, influencing astrocytes and microglia, and modulating glutamate release. Dysregulation of the eCBs may be responsible for deficits in synaptic plasticity and learning following TBI. Taken together, the existing evidence indicates eCBs may contribute to TBI manifestation, pathogenesis, and recovery, but it also suggests there may be a therapeutic role for the eCB system in TBI.

A Screen of Plant-Based Natural Products Revealed That Quercetin Prevents Pyroglutamylated Amyloid-ß (Aß3(pE)-42) Uptake in Astrocytes As Well As Resulting Astrogliosis and Synaptic Dysfunction.

Two connected histopathological hallmarks of Alzheimer's disease (AD) are chronic neuroinflammation and synaptic dysfunction. The accumulation of the most prevalent posttranslationally modified form of Aß1-42, pyroglutamylated amyloid-ß (Aß3(pE)-42) in astrocytes is directly linked to glial activation and the release of proinflammatory cytokines that in turn contribute to early synaptic dysfunction in AD. At present, the mechanisms of Aß3(pE)-42 uptake to astrocytes are unknown and pharmacological interventions that interfere with this process are not available. Here we developed a simple screening assay to identify substances from a plant extract library that prevent astroglial Aß3(pE)-42 uptake. We first show that this approach yields valid and reproducible results. Second, we show endocytosis of Aß3(pE)-42 oligomers by astrocytes and that quercetin, a plant flavonol, is effective to specifically block astrocytic buildup of oligomeric Aß3(pE)-42. Importantly, quercetin does not induce a general impairment of endocytosis. However, it efficiently protects against early synaptic dysfunction following exogenous Aß3(pE)-42 application.