scholarly journals Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Jennifer Kelschenbach ◽  
Hongxia He ◽  
Boe-Hyun Kim ◽  
Alejandra Borjabad ◽  
Chao-Jiang Gu ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Mouse Brain ◽  
Memory Impairment ◽  
Hippocampal Slices ◽  
Neuronal Loss ◽  
Long Term Potentiation ◽  
Protein Quantification ◽  
Inflammatory Factors ◽  
Monocytic Cells ◽  
The Brain

ABSTRACTHIV causes neurodegeneration and dementia in AIDS patients, but its function in milder cognitive impairments in virologically suppressed patients on antiretroviral therapy is unknown. Such patients are immunocompetent, have low peripheral and brain HIV burdens, and show minimal brain neuropathology. Using the model of HIV-related memory impairment in EcoHIV-infected conventional mice, we investigated the neurobiological and cognitive consequences of efficient EcoHIV expression in the mouse brain after intracerebral infection. HIV integrated and persisted in an expressed state in brain tissue, was detectable in brain monocytic cells, and caused neuroinflammatory responses and lasting spatial, working, and associative memory impairment. Systemic antiretroviral treatment prevented direct brain infection and memory dysfunction indicating the requirement for HIV expression in the brain for disease. Similarly inoculated murine leukemia virus used as a control replicated in mouse brain but not in monocytic cells and was cognitively benign, linking the disease to HIV-specific functions. Memory impairment correlated in real time with hippocampal dysfunction shown by defective long-term potentiation in hippocampal slicesex vivoand with diffuse synaptodendritic injury in the hippocampus reflected in significant reduction in microtubule-associated protein 2 and synapsin II staining. In contrast, there was no evidence of overt neuronal loss in this region as determined by neuron-specific nuclear protein quantification, TUNEL assay, and histological observations. Our results reveal a novel capacity of HIV to induce neuronal dysfunction and memory impairment independent of neurotoxicity, distinct from the neurotoxicity of HIV infection in dementia.IMPORTANCEHIV neuropathogenesis has been attributed in large measure to neurotoxicity of viral proteins and inflammatory factors produced by infected monocytic cells in the brain. We show here that HIV expression in mouse brain causes lasting memory impairment by a mechanism involving injury to hippocampal synaptodendritic arbors and neuronal function but not overt neuronal loss in the region. Our results mirror the observation of minimal neurodegeneration in cognitively impaired HIV patients on antiretroviral therapy and demonstrate that HIV is nonneurotoxic in certain brain abnormalities that it causes. If neurons comprising the cognition-related networks survive HIV insult, at least for some time, there is a window of opportunity for disease treatment.

scholarly journals Mechanisms of Neurodegeneration in Various Forms of Parkinsonism—Similarities and Differences

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 656
Author(s):  
Dariusz Koziorowski ◽  
Monika Figura ◽  
Łukasz M. Milanowski ◽  
Stanisław Szlufik ◽  
Piotr Alster ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Protein Gene ◽  
Clinical Presentation ◽  
Neuronal Loss ◽  
Corticobasal Degeneration ◽  
Inflammatory Factors ◽  
Parkinsonian Disorders ◽  
Genetic Features ◽  
The Brain

Parkinson's disease (PD), dementia with Lewy body (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA) belong to a group of neurodegenerative diseases called parkinsonian syndromes. They share several clinical, neuropathological and genetic features. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra- and intracellular accumulation of misfolded proteins. The parkinsonian diseases affect distinct areas of the brain. PD and MSA belong to a group of synucleinopathies that are characterized by the presence of fibrillary aggregates of α-synuclein protein in the cytoplasm of selected populations of neurons and glial cells. PSP is a tauopathy associated with the pathological aggregation of the microtubule associated tau protein. Although PD is common in the world's aging population and has been extensively studied, the exact mechanisms of the neurodegeneration are still not fully understood. Growing evidence indicates that parkinsonian disorders to some extent share a genetic background, with two key components identified so far: the microtubule associated tau protein gene (MAPT) and the α-synuclein gene (SNCA). The main pathways of parkinsonian neurodegeneration described in the literature are the protein and mitochondrial pathways. The factors that lead to neurodegeneration are primarily environmental toxins, inflammatory factors, oxidative stress and traumatic brain injury.

Priming-Induced Shift in Synaptic Plasticity in the Rat Hippocampus

1999 ◽  
Vol 82 (4) ◽  
pp. 2024-2028 ◽  
Author(s):  
Hongyan Wang ◽  
John J. Wagner
Keyword(s):  
Synaptic Plasticity ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Crossover Point ◽  
Term Potentiation ◽  
Before And After ◽  
History Of ◽  
The Brain ◽  
Dependent Mechanism

The activity history of a given neuron has been suggested to influence its future responses to synaptic input in one prominent model of experience-dependent synaptic plasticity proposed by Bienenstock, Cooper, and Munro (BCM theory). Because plasticity of synaptic plasticity (i.e., metaplasticity) is similar in concept to aspects of the BCM proposal, we have tested the possibility that a form of metaplasticity induced by a priming stimulation protocol might exhibit BCM-like characteristics. CA1 field excitatory postsynaptic potentials (EPSPs) obtained from rat hippocampal slices were used to monitor synaptic responses before and after conditioning stimuli (3–100 Hz) of the Schaffer collateral inputs. A substantial rightward shift (>5-fold) in the frequency threshold between long-term depression (LTD) and long-term potentiation (LTP) was observed <1 h after priming. This change in the LTD/P crossover point occurred at both primed and unprimed synaptic pathways. These results provide new support for the existence of a rapid, heterosynaptic, experience-dependent mechanism that is capable of modifying the synaptic plasticity phenomena that are commonly proposed to be important for developmental and learning/memory processes in the brain.

scholarly journals N-Docosahexanoylethanolamine Reduces Microglial Activation and Improves Hippocampal Plasticity in a Murine Model of Neuroinflammation

2020 ◽  
Vol 21 (24) ◽  
pp. 9703
Author(s):  
Anna Tyrtyshnaia ◽  
Anatoly Bondar ◽  
Sophia Konovalova ◽  
Ruslan Sultanov ◽  
Igor Manzhulo
Keyword(s):  
Synaptic Plasticity ◽  
Microglial Activation ◽  
Hippocampal Slices ◽  
Morphological Characteristics ◽  
Long Term Potentiation ◽  
Structural Analog ◽  
Neuronal Morphology ◽  
Hippocampal Neurogenesis ◽  
Inflammatory Factors ◽  
Negative Effect

Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top priorities of modern neurobiology. N-docosahexanoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analog of anandamide, an essential endocannabinoid produced from arachidonic acid. Our study aims to elucidate the pharmacological activity of synaptamide in lipopolysaccharide (LPS)-induced neuroinflammation. Memory deficits in animals were determined using behavioral tests. To study the effects of LPS (750 µg/kg/day, 7 days) and synaptamide (10 mg/kg/day, 7 days) on synaptic plasticity, long-term potentiation was examined in the CA1 area of acute hippocampal slices. The Golgi–Cox method allowed us to assess neuronal morphology. The production of inflammatory factors and receptors was assessed using ELISA and immunohistochemistry. During the study, functional, structural, and plastic changes within the hippocampus were identified. We found a beneficial effect of synaptamide on hippocampal synaptic plasticity and morphological characteristics of neurons. Synaptamide treatment recovered hippocampal neurogenesis, suppressed microglial activation, and significantly improved hippocampus-dependent memory. The basis of the phenomena described above is probably the powerful anti-inflammatory activity of synaptamide, as shown in our study and several previous works.

Sulforaphane Reverses the Amyloid-β Oligomers Induced Depressive-Like Behavior

2020 ◽  
Vol 78 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Wei Wang ◽  
Cuibai Wei ◽  
Meina Quan ◽  
Tingting Li ◽  
Jianping Jia
Keyword(s):  
Oxidative Stress ◽  
Memory Impairment ◽  
Molecular Mechanisms ◽  
Psychological Symptoms ◽  
Amyloid Β ◽  
Serotonergic System ◽  
Inflammatory Factors ◽  
The Relationship ◽  
The Brain ◽  
And Oxidative Stress

Background: Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer’s disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Objective: Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Methods: Male SD rats were administered amyloid-β oligomers (AβOs) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and anti-oxidative stress, was injected intraperitoneally to evaluate the therapeutic effect. Results: The results showed that AβOs induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. Conclusion: These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia.

NMDA-Independent LTP by Adenosine A2 Receptor-Mediated Postsynaptic AMPA Potentiation in Hippocampus

1997 ◽  
Vol 78 (4) ◽  
pp. 1965-1972 ◽  
Author(s):  
Kofi Kessey ◽  
David J. Mogul
Keyword(s):  
Synaptic Transmission ◽  
Ampa Receptor ◽  
Hippocampal Slices ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Common Mechanism ◽  
Excitatory Postsynaptic Potential ◽  
Ca1 Region ◽  
The Brain

Kessey, Kofi and David J. Mogul. NMDA-independent LTP by adenosine A2 receptor-mediated postsynaptic AMPA potentiation in hippocampus. J. Neurophysiol. 78: 1965–1972, 1997. The role of adenosine A2 receptors in normal synaptic transmission and tetanus-induced long-term potentiation (LTP) was tested by stimulation of the Schaffer collateral pathway and recording of the field excitatory postsynaptic potential (EPSP) in the CA1 region of rat transverse hippocampal slices. Activation of adenosine A2 receptors with the A2 agonist N 6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA; 20 nM) enhanced synaptic transmission during low-frequency test pulses (0.033 Hz). Paired stimulation before and during DPMA exposure indicated no paired-pulse facilitation as a result of A2 activation, suggesting that enhancement was not a result of presynaptic modulation. DPMA enhanced the early phase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component of the EPSP. In contrast, DPMA had no effect on the N-methyl-d-aspartate (NMDA) component isolated using low extracellular Mg2+ and the AMPA receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (20 μM), indicating that the effects of A2 activation on synaptic transmission were mediated by a postsynaptic enhancement of the AMPA response. Activation of adenosine A2 receptors during a brief tetanus (100 Hz, 1 s) increased the level of LTP by 36% over that seen in response to a tetanus under control conditions. DPMA exposure after prior induction of LTP showed no additional potentiation, indicating that the mechanisms that contribute to both types of increases in synaptic transmission share a common mechanism. A slow onset NMDA-independent LTP could be induced by application of a tetanus during perfusion of DPMA with the NMDA blocker AP5 (50 μM). Blockade of L-type Ca channels with nifedipine (10 μM) had no effect on normal synaptic transmission but reduced NMDA-independent LTP by 32%. Very little NMDA-independent LTP could be induced after prior saturation of NMDA-dependent LTP via multiple tetani spaced 10 min apart, indicating that both forms of LTP are eventually convergent on a common mechanism, presumably the postsynaptic AMPA receptor response. Because extracellular adenosine levels are modulated by cellular activity throughout the brain and because adenosine receptor activation can markedly alter levels of synaptic transmission independent of NMDA receptors, adenosine may play an important and complex role as a modulator of synaptic transmission in the brain.

scholarly journals Human Three-Finger Protein Lypd6 Is a Negative Modulator of the Cholinergic System in the Brain

2021 ◽  
Vol 9 ◽  
Author(s):  
Dmitrii Kulbatskii ◽  
Zakhar Shenkarev ◽  
Maxim Bychkov ◽  
Eugene Loktyushov ◽  
Mikhail Shulepko ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Cholinergic System ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Protein Docking ◽  
Water Soluble ◽  
Maximal Amplitude ◽  
The Brain ◽  
Α7 Nachrs ◽  
Negative Modulator

Lypd6 is a GPI-tethered protein from the Ly-6/uPAR family expressed in the brain. Lypd6 enhances the Wnt/β-catenin signaling, although its action on nicotinic acetylcholine receptors (nAChRs) have been also proposed. To investigate a cholinergic activity of Lypd6, we studied a recombinant water-soluble variant of the human protein (ws-Lypd6) containing isolated “three-finger” LU-domain. Experiments at different nAChR subtypes expressed in Xenopus oocytes revealed the negative allosteric modulatory activity of ws-Lypd6. Ws-Lypd6 inhibited ACh-evoked currents at α3β4- and α7-nAChRs with IC50 of ∼35 and 10 μM, respectively, and the maximal amplitude of inhibition of 30–50%. EC50 of ACh at α3β4-nAChRs (∼30 μM) was not changed in the presence of 35 μM ws-Lypd6, while the maximal amplitude of ACh-evoked current was reduced by ∼20%. Ws-Lypd6 did not elicit currents through nAChRs in the absence of ACh. Application of 1 μM ws-Lypd6 significantly inhibited (up to ∼28%) choline-evoked current at α7-nAChRs in rat hippocampal slices. Similar to snake neurotoxin α-bungarotoxin, ws-Lypd6 suppressed the long-term potentiation (LTP) in mouse hippocampal slices. Colocalization of endogenous GPI-tethered Lypd6 with α3β4- and α7-nAChRs was detected in primary cortical and hippocampal neurons. Ws-Lypd6 interaction with the extracellular domain of α7-nAChR was modeled using the ensemble protein-protein docking protocol. The interaction of all three Lypd6 loops (“fingers”) with the entrance to the orthosteric ligand-binding site and the loop C of the primary receptor subunit was predicted. The results obtained allow us to consider Lypd6 as the endogenous negative modulator involved in the regulation of the cholinergic system in the brain.

TRIM32 Deficiency Impairs Synaptic Plasticity by Excitatory-Inhibitory Imbalance via Notch Pathway

2020 ◽  
Vol 30 (8) ◽  
pp. 4617-4632
Author(s):  
Michael Ntim ◽  
Qi-Fa Li ◽  
Yue Zhang ◽  
Xiao-Da Liu ◽  
Na Li ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptors ◽  
Gaba Receptors ◽  
Hippocampal Slices ◽  
Notch Pathway ◽  
Long Term Potentiation ◽  
Notch Signaling Pathway ◽  
Autism Spectrum ◽  
Neural Basis ◽  
The Brain

Abstract Synaptic plasticity is the neural basis of physiological processes involved in learning and memory. Tripartite motif-containing 32 (TRIM32) has been found to play many important roles in the brain such as neural stem cell proliferation, neurogenesis, inhibition of nerve proliferation, and apoptosis. TRIM32 has been linked to several nervous system diseases including autism spectrum disorder, depression, anxiety, and Alzheimer’s disease. However, the role of TRIM32 in regulating the mechanism of synaptic plasticity is still unknown. Our electrophysiological studies using hippocampal slices revealed that long-term potentiation of CA1 synapses was impaired in TRIM32 deficient (KO) mice. Further research found that dendritic spines density, AMPA receptors, and synaptic plasticity-related proteins were also reduced. NMDA receptors were upregulated whereas GABA receptors were downregulated in TRIM32 deficient mice, explaining the imbalance in excitatory and inhibitory neurotransmission. This caused overexcitation leading to decreased neuronal numbers in the hippocampus and cortex. In summary, this study provides this maiden evidence on the synaptic plasticity changes of TRIM32 deficiency in the brain and proposes that TRIM32 relates the notch signaling pathway and its related mechanisms contribute to this deficit.

scholarly journals REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment

2020 ◽  
Vol 21 (24) ◽  
pp. 9482
Author(s):  
Jee Hyun Yi ◽  
Huiyoung Kwon ◽  
Eunbi Cho ◽  
Jieun Jeon ◽  
Jeongwon Lee ◽  
...  
Keyword(s):  
Memory Impairment ◽  
Hippocampal Slices ◽  
Amyloid Β ◽  
Neurological Dysfunction ◽  
Synaptic Dysfunction ◽  
Hairpin Rna ◽  
Damage Response ◽  
Acute Hippocampal Slices ◽  
The Brain ◽  
Ad Therapy

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy.

Neuro-AIDS: Current status and Challenges to Antiretroviral Drug Therapy (ART) for Its Treatment.

2020 ◽  
Vol 15 ◽  
Author(s):  
Smita P. Kakad ◽  
Sanjay J. Kshirsagar
Keyword(s):  
Nervous System ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Sensory Neuropathy ◽  
Current Status ◽  
Viral Reservoir ◽  
Viral Reservoirs ◽  
Highly Active ◽  
Aids Therapy ◽  
The Brain

Introduction: The infiltration of HIV into the brain alters the functions of the nervous system known as NeuroAIDS. It leads to neuronal defects clinically manifested by motor and cognitive dysfunctions. Materials/Methods: Current antiretroviral therapy can prevent viral replication but cannot cure the disease completely. HAART-Highly active antiretroviral therapy used for the treatment of HIV infection. Challenges in neuro-AIDS therapy are as shown in the graphical abstract. One of the challenges is latent viral reservoirs like the brain; which acts as a sanctuary site for viruses. Nearly ~50% of HIV patients show neuropathological signs. Nervous system related disorders including AIDS dementia, sensory neuropathy, and myelopathy have a 25% of prevalence in patients having access to a highly active combination antiretroviral therapy. Results/Conclusions: Brain is one of the viral sanctuary sites for HIV. The current need of neuro-AIDS therapy is to target the brain as a viral reservoir. Drugs should cross or bypass the blood-brain barrier to reach the brain with effective concentrations. Current research on novel drug delivery approaches may prove helpful to treat neuro-AIDS and related disorders effectively.

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