Modulation Of Synaptic Function Research Articles

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function.

Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function. In addition, LTA4H plasma levels are increased in both aging and Alzheimer's disease and correlated with cognitive impairment. These results identify a role for LTA4H in the brain, and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases.

Acupuncture Therapy on Dementia: Explained with an Integrated Analysis on Therapeutic Targets and Associated Mechanisms.

Dementia, mainly Alzheimer's disease (AD) and vascular dementia (VaD), remains a global health challenge. Previous studies have demonstrated the benefits of acupuncture therapy (AT) in improving dementia. Nevertheless, the therapeutic targets and integrated biological mechanisms involved remain ambiguous. To identify therapeutic targets and biological mechanisms of AT in treating dementia by integrated analysis strategy. By the identification of differentially expressed genes (DEGs) of AD, VaD, and molecular targets of AT active components, the acupuncture therapeutic targets associated with the biological response to AD and VaD were extracted. Therapeutic targets-based functional enrichment analysis was conducted, and multiple networks were constructed. AT-therapeutic crucial targets were captured by weighted gene co-expression network analysis (WGCNA). The interactions between crucial targets with AT active components were verified by molecular docking. Our results demonstrated that 132 and 76 acupuncture therapeutic targets were associated with AD and VaD. AT-therapeutic crucial targets including 58 for AD and 24 for VaD were captured by WGCNA, with 11 in shared, including NMU, GRP, TAC1, ADRA1D, and SST. In addition, 35 and 14 signaling pathways were significantly enriched by functional enrichment analysis, with 6 mutual pathways including neuroactive ligand-receptor interaction, GABAergic synapse, calcium signaling pathway, cAMP signaling pathway, chemokine signaling pathway, and inflammatory mediator regulation of TRP channels. The improvement of AD and VaD by AT was associated with modulation of synaptic function, immunity, inflammation, and apoptosis. Our study clarified the therapeutic targets of AT on dementia, providing valuable clues for complementing and combining pharmacotherapy.

Do Sleep Disturbances have a Dual Effect on Alzheimer's Disease?

Sleep disturbances and Alzheimer's disease have deleterious effects on various physiological and cognitive functions including synaptic plasticity, oxidative stress, neuroinflammation, and memory. In addition, clock genes expression is significantly altered following sleep disturbances, which may be involved in the pathogenesis of Alzheimer's disease. In this review article, we aimed to discuss the role of sleep disturbances and Alzheimer's disease in the regulation of synaptic plasticity, oxidative stress, neuroinflammation, and clock genes expression. Also, we aimed to find significant relationships between sleep disturbances and Alzheimer's disease in the modulation of these mechanisms. We referred to the controversial effects of sleep disturbances (particularly those related to the duration of sleep deprivation) on the modulation of synaptic function and neuroinflammation. We aimed to know that, do sleep disturbances have a dual effect on the progression of Alzheimer's disease? Although numerous studies have discussed the association between sleep disturbances and Alzheimer's disease, the new point of this study was to focus on the controversial effects of sleep disturbances on different biological functions, and to evaluate the potential dualistic role of sleep disturbances in the pathogenesis of Alzheimer's disease.

The far-reaching HAND of cART: cART effects on astrocytes.

Following the introduction of combination antiretroviral therapy (cART), the morbidity and mortality from human immunodeficiency virus (HIV) infection has been drastically curtailed and HIV has now become a chronic manageable disease. Persons living with HIV (PLWH) are living longer and experiencing significant co-morbidities and conditions of aging. NeuroHIV, clinically defined as HIV-Associated Neurocognitive Disorders (HAND) and pathologically manifested by persistent inflammation in the CNS despite cART, is a significant co-morbid condition for PLWH. In the pre-cART era, HIV mediated much of the pathogenesis in the Central Nervous System (CNS); in the cART era, with low to undetectable viremia, other mechanisms may be contributing to persistent neuroinflammation. Emerging data point to the adverse effects at the cellular level of cART, independent of HIV. Astrocytes are the most abundant cells in the CNS, playing vital roles in maintaining CNS homeostasis (e.g. metabolic support to neurons, clearance of neurotransmitters, ion balance, modulation of synaptic functions and maintaining the structural integrity of the blood brain barrier (BBB). Therefore, any disruption of their function will have wide repercussions in the CNS. In this review, we will address current knowledge and gaps on the impact of antiretrovirals (ARVs) on astrocytes and physiologic consequences in the CNS. Understanding the status of this field, will provide a practical framework to elucidate the potential role of cART-mediated dysregulation of astrocytes in neuroHIV pathogenesis and inform therapeutic strategies that are "neuro-friendly". Graphical abstract CNS-penetrating cART have the potential to cause resting astrocytes to become activated into an A1 or neurotoxic phenotype. These cells can in turn secrete inflammatory cytokines that affect surrounding microglia macrophages, as well as neurotoxic factors that impact nearby neurons. In addition, impairment in the physiologic functions of astrocytes will result in altered BBB permeability and disrupted metabolic homeostasis. CNS=Central Nervous System; cART=combined antiretroviral therapy; BBB=blood brain barrier.

Vitamin A: its many roles-from vision and synaptic plasticity to infant mortality.

The recognition that a dietary factor is essential to maintain good and sensitive vision as well as overall health goes back over 3,000years to the ancient Egyptians. With the discovery of the vitamins at the turn of the twentieth century, fat-soluble vitamin A was soon shown to be the essential factor. In the first half of the twentieth century, the role vitamin A plays in vision, as precursor to the light-sensitive visual pigment molecules in the photoreceptors was elegantly worked out, especially by George Wald and his colleagues. Beginning in the 1960s, with the recognition of the active metabolite of vitamin A, its acid form now called retinoic acid, the roles of vitamin A in maintaining overall health of an organism began to be explored, and this research continues to this day. Receptors activated by retinoic acid, the RARs and RXRs have been shown to regulate gene transcription in a surprisingly wide variety of biological processes from early growth and development to the maintenance of epithelial tissues in many organs, the regulation of the immune system, and even the modulation of synaptic function in the brain involved in mechanisms underlying memory and learning. Therapeutic uses for retinoic acid have been developed, including one for a specific form of leukemia. The story is by no means complete and it is likely more surprises await with regard to this remarkable molecule.

Amyloid Precursor Protein (APP) and GABAergic Neurotransmission.

The amyloid precursor protein (APP) is the parent polypeptide from which amyloid-beta (Aβ) peptides, key etiological agents of Alzheimer’s disease (AD), are generated by sequential proteolytic processing involving β- and γ-secretases. APP mutations underlie familial, early-onset AD, and the involvement of APP in AD pathology has been extensively studied. However, APP has important physiological roles in the mammalian brain, particularly its modulation of synaptic functions and neuronal survival. Recent works have now shown that APP could directly modulate γ-aminobutyric acid (GABA) neurotransmission in two broad ways. Firstly, APP is shown to interact with and modulate the levels and activity of the neuron-specific Potassium-Chloride (K+-Cl−) cotransporter KCC2/SLC12A5. The latter is key to the maintenance of neuronal chloride (Cl−) levels and the GABA reversal potential (EGABA), and is therefore important for postsynaptic GABAergic inhibition through the ionotropic GABAA receptors. Secondly, APP binds to the sushi domain of metabotropic GABAB receptor 1a (GABABR1a). In this regard, APP complexes and is co-transported with GABAB receptor dimers bearing GABABR1a to the axonal presynaptic plasma membrane. On the other hand, secreted (s)APP generated by secretase cleavages could act as a GABABR1a-binding ligand that modulates presynaptic vesicle release. The discovery of these novel roles and activities of APP in GABAergic neurotransmission underlies the physiological importance of APP in postnatal brain function.

In vivo Ca2+ imaging of astrocytic microdomains reveals a critical role of the amyloid precursor protein for mitochondria.

The investigation of amyloid precursor protein (APP) has been mainly confined to its neuronal functions, whereas very little is known about its physiological role in astrocytes. Astrocytes exhibit a particular morphology with slender extensions protruding from somata and primary branches. Along these fine extensions, spontaneous calcium transients occur in spatially restricted microdomains. Within these microdomains mitochondria are responsible for local energy supply and Ca2+ buffering. Using two-photon in vivo Ca2+ imaging, we report a significant decrease in the density of active microdomains, frequency of spontaneous Ca2+ transients and slower Ca2+ kinetics in mice lacking APP. Mechanistically, these changes could be potentially linked to mitochondrial malfunction as our in vivo and in vitro data revealed severe, APP-dependent structural mitochondrial fragmentation in astrocytes. Functionally, such mitochondria exhibited prolonged kinetics and morphology dependent signal size of ATP-induced Ca2+ transients. Our results highlight a prominent role of APP in the modulation of Ca2+ activity in astrocytic microdomains whose precise functioning is crucial for the reinforcement and modulation of synaptic function. This study provides novel insights in APP physiological functions which are important for the understanding of the effects of drugs validated in Alzheimer's disease treatment that affect the function of APP.

UBE3A and Its Link With Autism.

UBE3A is a dual function protein consisting of ubiquitin ligase as well as transcriptional co-activator function. UBE3A gene is imprinted in the brain with preferential maternal-specific expression particularly in the neuron and loss of activity of the maternally inherited UBE3A causes Angelman syndrome (AS), characterized by severe mental retardation, lack of speech, seizures and autistic features. Interestingly, duplication, triplication, or gain-of-function mutations in the UBE3A gene are also linked with autism clinically distinguished by social impairments and stereotyped behaviors. These findings indicate that the expression and activity of UBE3A must be tightly regulated during brain development and UBE3A might be playing a crucial role in controlling synaptic function and plasticity through proteasome-mediated degradation as well as transcriptional regulation of its target proteins. In fact, several recent reports demonstrated the role of UBE3A in the modulation of synaptic function and plasticity. This review focuses on the critical role of UBE3A in regulating the synaptic function and how its altered activity is associated with autism.

Metabotropic Glutamate Receptor 7: From Synaptic Function to Therapeutic Implications.

Metabotropic glutamate receptor 7 (mGluR7) is localized presynaptically at the active zone of neurotransmitter release. Unlike mGluR4 and mGluR8, which share mGluR7’s presynaptic location, mGluR7 shows low affinity for glutamate and is activated only by high glutamate concentrations. Its wide distribution in the central nervous system (CNS) and evolutionary conservation across species suggest that mGluR7 plays a primary role in controlling excitatory synapse function. High mGluR7 expression has been observed in several brain regions that are critical for CNS functioning and are involved in neurological and psychiatric disorder development. Until the recent discovery of selective ligands for mGluR7, techniques to elucidate its role in neural function were limited to the use of knockout mice and gene silencing. Studies using these two techniques have revealed that mGluR7 modulates emotionality, stress and fear responses. N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) was reported as the first selective mGluR7 allosteric agonist. Pharmacological effects of AMN082 have not completely confirmed the mGluR7-knockout mouse phenotype; this has been attributed to rapid receptor internalization after drug treatment and to the drug’s apparent lack of in vivo selectivity. Therefore, the more recently developed mGluR7 negative allosteric modulators (NAMs) are crucial for understanding mGluR7 function and for exploiting its potential as a target for therapeutic interventions. This review presents the main findings regarding mGluR7’s effect on modulation of synaptic function and its role in normal CNS function and in models of neurologic and psychiatric disorders.

Lights On for the Molecular Players of Presynaptic Plasticity

Neuronal response or adaption to a changing environment relies on the modulation of synaptic function. How this modulation is achieved remains controversial. In this issue of Neuron, Sugie et al. (2015) now report that active zones of Drosophila photoreceptors undergo activity-dependent changes in their molecular composition.

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like α-neurexins (α-Nrxn) and their extracellular binding partners determine synapse function. Although α-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an α-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABAB receptor (GABA(B)R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABA(B)R, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABA(B)R. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABA(B)R with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABA(A)R with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABA(B)R and postsynaptic GABA(A)R. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA(A)R and GABA(B)R subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors.

Jelly belly trans‐synaptic signaling to anaplastic lymphoma kinase regulates neurotransmission strength and synapse architecture

In Drosophila, the secreted signaling molecule Jelly Belly (Jeb) activates anaplastic lymphoma kinase (Alk), a receptor tyrosine kinase, in multiple developmental and adult contexts. We have shown previously that Jeb and Alk are highly enriched at Drosophila synapses within the CNS neuropil and neuromuscular junction (NMJ) and postulated a conserved intercellular signaling function. At the embryonic and larval NMJ, Jeb is localized in the motor neuron presynaptic terminal whereas Alk is concentrated in the muscle postsynaptic domain surrounding boutons, consistent with anterograde trans-synaptic signaling. Here, we show that neurotransmission is regulated by Jeb secretion by functional inhibition of Jeb-Alk signaling. Jeb is a novel negative regulator of neuromuscular transmission. Reduction or inhibition of Alk function results in enhanced synaptic transmission. Activation of Alk conversely inhibits synaptic transmission. Restoration of wild-type postsynaptic Alk expression in Alk partial loss-of-function mutants rescues NMJ transmission phenotypes and confirms that postsynaptic Alk regulates NMJ transmission. The effects of impaired Alk signaling on neurotransmission are observed in the absence of associated changes in NMJ structure. Complete removal of Jeb in motor neurons, however, disrupts both presynaptic bouton architecture and postsynaptic differentiation. Nonphysiologic activation of Alk signaling also negatively regulates NMJ growth. Activation of Jeb-Alk signaling triggers the Ras-MAP kinase cascade in both pre- and postsynaptic compartments. These novel roles for Jeb-Alk signaling in the modulation of synaptic function and structure have potential implications for recently reported Alk functions in human addiction, retention of spatial memory, cognitive dysfunction in neurofibromatosis, and pathogenesis of amyotrophic lateral sclerosis.

Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P2and PI(5)P

Normal steady-state levels of the signalling lipids PI(3,5)P(2) and PI(5)P require the lipid kinase FAB1/PIKfyve and its regulators, VAC14 and FIG4. Mutations in the PIKfyve/VAC14/FIG4 pathway are associated with Charcot-Marie-Tooth syndrome and amyotrophic lateral sclerosis in humans, and profound neurodegeneration in mice. Hence, tight regulation of this pathway is critical for neural function. Here, we examine the localization and physiological role of VAC14 in neurons. We report that endogenous VAC14 localizes to endocytic organelles in fibroblasts and neurons. Unexpectedly, VAC14 exhibits a pronounced synaptic localization in hippocampal neurons, suggesting a role in regulating synaptic function. Indeed, the amplitude of miniature excitatory postsynaptic currents is enhanced in both Vac14(-/-) and Fig4(-/-) neurons. Re-introduction of VAC14 in postsynaptic Vac14(-/-) cells reverses this effect. These changes in synaptic strength in Vac14(-/-) neurons are associated with enhanced surface levels of the AMPA-type glutamate receptor subunit GluA2, an effect that is due to diminished regulated endocytosis of AMPA receptors. Thus, VAC14, PI(3,5)P(2) and/or PI(5)P play a role in controlling postsynaptic function via regulation of endocytic cycling of AMPA receptors.

Tuning synaptic transmission in the hippocampus by stress: the CRH system

To enhance survival, an organism needs to remember—and learn from—threatening or stressful events. This fact necessitates the presence of mechanisms by which stress can influence synaptic transmission in brain regions, such as hippocampus, that subserve learning and memory. A major focus of this series of monographs is on the role and actions of adrenal-derived hormones, corticosteroids, and of brain-derived neurotransmitters, on synaptic function in the stressed hippocampus. Here we focus on the contribution of hippocampus-intrinsic, stress-activated CRH-CRH receptor signaling to the function and structure of hippocampal synapses. Corticotropin-releasing hormone (CRH) is expressed in interneurons of adult hippocampus, and is released from axon terminals during stress. The peptide exerts time- and dose-dependent effects on learning and memory via modulation of synaptic function and plasticity. Whereas physiological levels of CRH, acting over seconds to minutes, augment memory processes, exposure to presumed severe-stress levels of the peptide results in spine retraction and loss of synapses over more protracted time-frames. Loss of dendritic spines (and hence of synapses) takes place through actin cytoskeleton collapse downstream of CRHR1 receptors that reside within excitatory synapses on spine heads. Chronic exposure to stress levels of CRH may promote dying-back (atrophy) of spine-carrying dendrites. Thus, the acute effects of CRH may contribute to stress-induced adaptive mechanisms, whereas chronic or excessive exposure to the peptide may promote learning problems and premature cognitive decline.

Regulation of GABAA Receptor Dynamics by Interaction with Purinergic P2X2 Receptors

γ-Aminobutyric acid type A receptors (GABA(A)Rs) in the spinal cord are evolving as an important target for drug development against pain. Purinergic P2X(2) receptors (P2X(2)Rs) are also expressed in spinal cord neurons and are known to cross-talk with GABA(A)Rs. Here, we investigated a possible "dynamic" interaction between GABA(A)Rs and P2X(2)Rs using co-immunoprecipitation and fluorescence resonance energy transfer (FRET) studies in human embryonic kidney (HEK) 293 cells along with co-localization and single particle tracking studies in spinal cord neurons. Our results suggest that a significant proportion of P2X(2)Rs forms a transient complex with GABA(A)Rs inside the cell, thus stabilizing these receptors and using them for co-trafficking to the cell surface, where P2X(2)Rs and GABA(A)Rs are primarily located extra-synaptically. Furthermore, agonist-induced activation of P2X(2)Rs results in a Ca(2+)-dependent as well as an apparently Ca(2+)-independent increase in the mobility and an enhanced degradation of GABA(A)Rs, whereas P2X(2)Rs are stabilized and form larger clusters. Antagonist-induced blocking of P2XRs results in co-stabilization of this receptor complex at the cell surface. These results suggest a novel mechanism where association of P2X(2)Rs and GABA(A)Rs could be used for specific targeting to neuronal membranes, thus providing an extrasynaptic receptor reserve that could regulate the excitability of neurons. We further conclude that blocking the excitatory activity of excessively released ATP under diseased state by P2XR antagonists could simultaneously enhance synaptic inhibition mediated by GABA(A)Rs.

Therapeutic Exploration of Metabotropic Glutamate Receptor Antagonists in Parkinson’s Disease by Positron Emission Tomography

Metabotropic glutamate receptors (mGluR)s are G-protein-coupled receptors that function as modulators of synaptic function and glutamate transmission. Post-synaptically localized subtype 5 mGlu5 receptors are co-localized with adenosine A2a, dopamine, and N-methyl-D-aspartate (NMDA) receptors and regulate local protein synthesis and messenger RNA (mRNA) translation at synapses, and are thus ideally positioned to control synaptic plasticity. Aberrant synaptic plasticity appears to be involved in a number of developmental and degenerative neuropsychiatric disorders, including Parkinson’s disease. Pharmacological modulation of mGluR5 could potentially open new therapeutic avenues for the treatment of such disorders, for both symptomatic and neuroprotective purposes. In this review, we summarize a series ofin vivostudies we performed in order to delineate the anatomical basis and functional role of mGluR5 antagonists in Parkinson’s disease models, taking advantage of high-resolution positron emission tomography (PET) and the recent development of novel specific radiopharmaceuticals. Our findings of a prevalent distribution of mGluR5 in the striatum and limbic structures and a significant binding enhancement following dopamine lesions support the role of mGlu5 receptors in modulating dopamine- and glutamate-dependent signaling and synaptic plasticity within the basal ganglia cortico–subcortical loops.

Modulation of synaptic function by extracellular tau enriched in oligomers

Modulation of synaptic function by extracellular tau enriched in oligomers

Distinctive roles of different β‐amyloid 42 aggregates in modulation of synaptic functions

To determine how endogenously secreted beta-amyloid 42 (Abeta42) aggregates regulate synaptic functions, we examined effects of Abeta42 at the neuromuscular junction of Drosophila larvae. Voltage-clamp recordings of synaptic transmission and optical analysis of vesicle recycling at presynaptic terminals show that expression of Abeta42 in neurons leads to a reduction of neurotransmitter release. However, expression of Abeta42 in postsynaptic muscle cells enhanced neurotransmitter release. Both effects are neutralized by Abeta antibody, suggesting a role for secreted Abeta42 peptides. Application of exogenously prepared Abeta42 oligomers leads to a reduction in synaptic responses, whereas mixed Abeta42 aggregates with mainly fibrils elicit an opposite effect by increasing synaptic transmission. Further analysis of long-term depression (LTD) confirms differential effects of different Abeta42 aggregates. Taken together, our data suggest that Abeta42 is secreted from neurons primarily as oligomers that inhibit neurotransmitter release and exert no effect on LTD. Whereas larger-sized aggregates, possibly fibrils, are major components secreted from muscle cells, which enhance synaptic transmission and LTD. Thus, different types of cells may secrete distinct forms of Abeta42 aggregates, leading to different modulation of synaptic functions.

A Role for Retinoic Acid in Homeostatic Plasticity

Prolonged changes in neuronal activity trigger compensatory modifications in synaptic function to restore firing rates to normal levels. In this issue of Neuron, Aoto et al. demonstrate that synthesis of retinoic acid offsets chronic network inactivity by increasing synaptic strength through upregulation of GluR1 receptors.

The quest for treatment of cognitive impairment: AMPA and mGlu5 receptor modulators

Background: Modulation of synaptic functions holds great potential as therapeutic strategies to manage neurodegenerative disorders in which cognitive functions are usually impaired as a core symptom of the disorders. The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) and subtype 5 metabotropic glutamate receptors (mGluR5s) are critically involved in a variety of cognitive functions and deficits and their selective modulators may be developed into effective drugs for enhancing cognition and reducing cognitive deficits. Objective: This short review covers recent advances in research development of AMPAR and mGluR5 modulators as potential therapeutics for the treatment of cognitive impairment. Results/conclusion: Selective modulators of AMPARs and mGluR5s possess several advantages over the receptor agonists/antagonists as potential novel therapeutics for cognitive impairment. Positive allosteric modulators have potential therapeutic value in correcting the glutamatergic hypofunction associated with some cognitive disorders without inducing neuronal excitotoxicity. Their negative modulators, on the other hand, reduce excessive glutamatergic activity without shutting down the neural circuits as the AMPAR antagonists do. Further studies are, however, needed, particularly those with in vivo utility evaluation.