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1.
Nat Commun ; 12(1): 5220, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471104

RESUMO

Advancement in human induced pluripotent stem cell (iPSC) neuron and microglial differentiation protocols allow for disease modeling using physiologically relevant cells. However, iPSC differentiation and culturing protocols have posed challenges to maintaining consistency. Here, we generated an automated, consistent, and long-term culturing platform of human iPSC neurons, astrocytes, and microglia. Using this platform we generated a iPSC AD model using human derived cells, which showed signs of Aß plaques, dystrophic neurites around plaques, synapse loss, dendrite retraction, axon fragmentation, phospho-Tau induction, and neuronal cell death in one model. We showed that the human iPSC microglia internalized and compacted Aß to generate and surround the plaques, thereby conferring some neuroprotection. We investigated the mechanism of action of anti-Aß antibodies protection and found that they protected neurons from these pathologies and were most effective before pTau induction. Taken together, these results suggest that this model can facilitate target discovery and drug development efforts.


Assuntos
Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Diferenciação Celular , Humanos , Cinética , Placa Amiloide , Sinapses/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445216

RESUMO

Locomotion results in an alternance of flexor and extensor muscles between left and right limbs generated by motoneurons that are controlled by the spinal interneuronal circuit. This spinal locomotor circuit is modulated by sensory afferents, which relay proprioceptive and cutaneous inputs that inform the spatial position of limbs in space and potential contacts with our environment respectively, but also by supraspinal descending commands of the brain that allow us to navigate in complex environments, avoid obstacles, chase prey, or flee predators. Although signaling pathways are important in the establishment and maintenance of motor circuits, the role of DSCAM, a cell adherence molecule associated with Down syndrome, has only recently been investigated in the context of motor control and locomotion in the rodent. DSCAM is known to be involved in lamination and delamination, synaptic targeting, axonal guidance, dendritic and cell tiling, axonal fasciculation and branching, programmed cell death, and synaptogenesis, all of which can impact the establishment of motor circuits during development, but also their maintenance through adulthood. We discuss herein how DSCAM is important for proper motor coordination, especially for breathing and locomotion.


Assuntos
Axônios/metabolismo , Moléculas de Adesão Celular/metabolismo , Locomoção , Músculo Esquelético/metabolismo , Mecânica Respiratória , Sinapses/metabolismo , Animais , Apoptose , Moléculas de Adesão Celular/genética , Síndrome de Down/genética , Síndrome de Down/metabolismo , Humanos , Sinapses/genética
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445628

RESUMO

We investigated the alterations of hippocampal and reticulo-thalamic (RT) GABAergic parvalbumin (PV) interneurons and their synaptic re-organizations underlying the prodromal local sleep disorders in the distinct rat models of Parkinson's disease (PD). We demonstrated for the first time that REM sleep is a predisposing state for the high-voltage sleep spindles (HVS) induction in all experimental models of PD, particularly during hippocampal REM sleep in the hemiparkinsonian models. There were the opposite underlying alterations of the hippocampal and RT GABAergic PV+ interneurons along with the distinct MAP2 and PSD-95 expressions. Whereas the PD cholinopathy enhanced the number of PV+ interneurons and suppressed the MAP2/PSD-95 expression, the hemiparkinsonism with PD cholinopathy reduced the number of PV+ interneurons and enhanced the MAP2/PSD-95 expression in the hippocampus. Whereas the PD cholinopathy did not alter PV+ interneurons but partially enhanced MAP2 and suppressed PSD-95 expression remotely in the RT, the hemiparkinsonism with PD cholinopathy reduced the PV+ interneurons, enhanced MAP2, and did not change PSD-95 expression remotely in the RT. Our study demonstrates for the first time an important regulatory role of the hippocampal and RT GABAergic PV+ interneurons and the synaptic protein dynamic alterations in the distinct rat models of PD neuropathology.


Assuntos
Modelos Animais de Doenças , Hipocampo/patologia , Interneurônios/patologia , Doença de Parkinson/complicações , Parvalbuminas/metabolismo , Transtornos do Sono-Vigília/patologia , Sinapses/patologia , Animais , Proteína 4 Homóloga a Disks-Large/genética , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropatologia , Ratos , Ratos Wistar , Formação Reticular/metabolismo , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/metabolismo , Sinapses/metabolismo , Tálamo/metabolismo , Ácido gama-Aminobutírico/metabolismo
4.
Nat Commun ; 12(1): 5083, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426577

RESUMO

AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of transmission. Changes in AMPAR localisation can enact synaptic plasticity, allowing long-term information storage, and is therefore tightly controlled. Multiple mechanisms regulating AMPAR synaptic anchoring have been described, but with limited coherence or comparison between reports, our understanding of this process is unclear. Here, combining synaptic recordings from mouse hippocampal slices and super-resolution imaging in dissociated cultures, we compare the contributions of three AMPAR interaction domains controlling transmission at hippocampal CA1 synapses. We show that the AMPAR C-termini play only a modulatory role, whereas the extracellular N-terminal domain (NTD) and PDZ interactions of the auxiliary subunit TARP γ8 are both crucial, and each is sufficient to maintain transmission. Our data support a model in which γ8 accumulates AMPARs at the postsynaptic density, where the NTD further tunes their positioning. This interplay between cytosolic (TARP γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity.


Assuntos
Região CA1 Hipocampal/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Sequência de Aminoácidos , Animais , Corantes Fluorescentes/metabolismo , Imageamento Tridimensional , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Mutação/genética , Plasticidade Neuronal , Neurônios/metabolismo , Ligação Proteica , Domínios Proteicos , Multimerização Proteica , Receptores de AMPA/química , Transmissão Sináptica
5.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360929

RESUMO

Complexins (Cplxs) 1 to 4 are components of the presynaptic compartment of chemical synapses where they regulate important steps in synaptic vesicle exocytosis. In the retina, all four Cplxs are present, and while we know a lot about Cplxs 3 and 4, little is known about Cplxs 1 and 2. Here, we performed in situ hybridization experiments and bioinformatics and exploited Cplx 1 and Cplx 2 single-knockout mice combined with immunocytochemistry and light microscopy to characterize in detail the cell type and synapse-specific distribution of Cplx 1 and Cplx 2. We found that Cplx 2 and not Cplx 1 is the main isoform expressed in normal and displaced amacrine cells and ganglion cells in mouse retinae and that amacrine cells seem to operate with a single Cplx isoform at their conventional chemical synapses. Surprising was the finding that retinal function, determined with electroretinographic recordings, was altered in Cplx 1 but not Cplx 2 single-knockout mice. In summary, the results provide an important basis for future studies on the function of Cplxs 1 and 2 in the processing of visual signals in the mammalian retina.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Células Amácrinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células Fotorreceptoras/metabolismo , Células Bipolares da Retina/metabolismo , Células Ganglionares da Retina/metabolismo , Células Horizontais da Retina/metabolismo , Proteínas SNARE/metabolismo , Sinapses/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Células Cultivadas , Biologia Computacional/métodos , Eletrorretinografia/métodos , Feminino , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética
6.
Neuroscience ; 472: 35-50, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34364953

RESUMO

G-protein-coupled-estrogen-receptor 1 (GPER1) is a membrane-bound receptor that mediates estrogen signaling via intracellular signaling cascades. We recently showed that GPER1 promotes the distal dendritic enrichment of hyperpolarization activated and cyclic nucleotide-gated (HCN)1 channels in CA1 stratum lacunosum-moleculare (SLM), suggesting a role of GPER1-mediated signaling in neuronal plasticity. Here we studied whether this role involves processes of structural plasticity, such as the regulation of spine and synapse density in SLM. In organotypic entorhino-hippocampal cultures from mice expressing eGFP, we analyzed spine densities in SLM after treatment with GPER1 agonist G1 (20 nM). G1 significantly increased the density of "non-stubby" spines (maturing spines with a spine head and a neck), but did so only in cultures from female mice. In support of this finding, the expression of synaptic proteins was sex-specifically altered in the cultures: G1 increased the protein (but not mRNA) expression of PSD95 and reduced the p-/n-cofilin ratio only in cultures from females. Application of E2 (2 nM) reproduced the sex-specific effect on spine density in SLM, but only partially on the expression of synaptic proteins. Spine synapse density was, however, not altered after G1-treatment, suggesting that the increased spine density did not translate into an increased spine synapse density in the culture model. Taken together, our results support a role of GPER1 in mediating structural plasticity in CA1 SLM, but suggest that in developing hippocampus, this role is sex-specific.


Assuntos
Hipocampo , Receptores de Estrogênio , Animais , Espinhas Dendríticas/metabolismo , Feminino , Proteínas de Ligação ao GTP , Hipocampo/metabolismo , Masculino , Camundongos , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G , Sinapses/metabolismo
7.
Nat Commun ; 12(1): 5040, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413305

RESUMO

SMN is a ubiquitously expressed protein and is essential for life. SMN deficiency causes the neurodegenerative disease spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. SMN interacts with itself and other proteins to form a complex that functions in the assembly of ribonucleoproteins. SMN is modified by SUMO (Small Ubiquitin-like Modifier), but whether sumoylation is required for the functions of SMN that are relevant to SMA pathogenesis is not known. Here, we show that inactivation of a SUMO-interacting motif (SIM) alters SMN sub-cellular distribution, the integrity of its complex, and its function in small nuclear ribonucleoproteins biogenesis. Expression of a SIM-inactivated mutant of SMN in a mouse model of SMA slightly extends survival rate with limited and transient correction of motor deficits. Remarkably, although SIM-inactivated SMN attenuates motor neuron loss and improves neuromuscular junction synapses, it fails to prevent the loss of sensory-motor synapses. These findings suggest that sumoylation is important for proper assembly and function of the SMN complex and that loss of this post-translational modification impairs the ability of SMN to correct selective deficits in the sensory-motor circuit of SMA mice.


Assuntos
Neurônios Motores/metabolismo , Atrofia Muscular Espinal/patologia , Doenças Neurodegenerativas/patologia , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Proteínas do Complexo SMN/metabolismo , Sumoilação , Sinapses/metabolismo , Animais , Animais Geneticamente Modificados , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Neurônios Motores/patologia , Atrofia Muscular Espinal/metabolismo , Doenças Neurodegenerativas/metabolismo , Sinapses/patologia , Peixe-Zebra
8.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445137

RESUMO

Disrupted glutamate clearance in the synaptic cleft leads to synaptic dysfunction and neurological diseases. Decreased glutamate removal from the synaptic cleft is known to cause excitotoxicity. Data on the physiological effects of increased glutamate clearance are contradictory. This study investigated the consequences of ceftriaxone (CTX), an enhancer of glutamate transporter 1 expression, treatment on long-term synaptic potentiation (LTP) in the hippocampus of young rats. In this study, 5-day administration of CTX (200 mg/kg) significantly weakened LTP in CA3-CA1 synapses. As shown by electrophysiological recordings, LTP attenuation was associated with weakening of N-Methyl-D-aspartate receptor (NMDAR)-dependent signaling in synapses. However, PCR analysis did not show downregulation of NMDAR subunits or changes in the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. We assume that extracellular burst stimulation activates fewer synapses in CTX-treated animals because increased glutamate reuptake results in reduced spillover, and neighboring synapses do not participate in neurotransmission. Attenuation of LTP was not accompanied by noticeable behavioral changes in the CTX group, with no behavioral abnormalities observed in the open field test or Morris water maze test. Thus, our experiments show that increased glutamate clearance can impair long-term synaptic plasticity and that this phenomenon can be considered a potential side effect of CTX treatment.


Assuntos
Ceftriaxona/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo
9.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445376

RESUMO

Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.


Assuntos
Ketamina/administração & dosagem , Fenóis/administração & dosagem , Piperidinas/administração & dosagem , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Animais , Injeções Intraperitoneais , Ketamina/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fenóis/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
10.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204581

RESUMO

Parkinson's disease (PD) is considered the most common disorder of synucleinopathy, which is characterised by intracellular inclusions of aggregated and misfolded α-synuclein (α-syn) protein in various brain regions, and the loss of dopaminergic neurons. During the early prodromal phase of PD, synaptic alterations happen before cell death, which is linked to the synaptic accumulation of toxic α-syn specifically in the presynaptic terminals, affecting neurotransmitter release. The oligomers and protofibrils of α-syn are the most toxic species, and their overexpression impairs the distribution and activation of synaptic proteins, such as the SNARE complex, preventing neurotransmitter exocytosis and neuronal synaptic communication. In the last few years, the role of the immune system in PD has been increasingly considered. Microglial and astrocyte activation, the gene expression of proinflammatory factors, and the infiltration of immune cells from the periphery to the central nervous system (CNS) represent the main features of the inflammatory response. One of the actors of these processes is α-syn accumulation. In light of this, here, we provide a systematic review of PD-related α-syn and inflammation inter-players.


Assuntos
Suscetibilidade a Doenças , Doença de Parkinson/metabolismo , Sinapses/metabolismo , alfa-Sinucleína/metabolismo , Imunidade Adaptativa , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Imunidade Inata , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Sinapses/imunologia , alfa-Sinucleína/genética
11.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34301746

RESUMO

Highlighted Research Paper: AMPA Receptors Exist in Tunable Mobile and Immobile Synaptic Fractions In Vivo, by Haiwen Chen, Richard H. Roth, Elena Lopez-Ortega, Han L. Tan, and Richard L. Huganir.


Assuntos
Hipocampo , Receptores de AMPA , Sinapses , Hipocampo/metabolismo , Receptores de AMPA/metabolismo , Sinapses/metabolismo
12.
Biophys J ; 120(16): 3409-3417, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34214532

RESUMO

Repetitive stimulation of excitatory synapses triggers molecular events required for signal transfer across neuronal synapses. It has been hypothesized that one of these molecular events, the diffusion of extrasynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPARs) (i.e., the diffusion hypothesis), is necessary to help synapses recover from paired-pulse depression. To examine this presumed role of AMPAR diffusion during repetitive presynaptic stimulation, a biophysical model based on published physiological results was developed to track the localization and gating of each AMPAR. The model demonstrates that AMPAR gating in short intervals of fewer than 100 ms is controlled by their position in relation to the glutamate release site and by their recovery from desensitization, but it is negligibly influenced by their diffusion. Therefore, these simulations failed to demonstrate a role for AMPAR diffusion in helping synapses recover from paired-pulse depression.


Assuntos
Hipocampo , Receptores de AMPA , Potenciais Pós-Sinápticos Excitadores , Hipocampo/metabolismo , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Transmissão Sináptica
13.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326063

RESUMO

The ability of neurons to produce behaviorally relevant activity in the absence of pathology relies on the fine balance of synaptic inhibition to excitation. In the hippocampal CA1 microcircuit, this balance is maintained by a diverse population of inhibitory interneurons that receive largely similar glutamatergic afferents as their target pyramidal cells, with EPSCs generated by both AMPA receptors (AMPARs) and NMDA receptors (NMDARs). In this study, we take advantage of a recently generated GluN2A-null rat model to assess the contribution of GluN2A subunits to glutamatergic synaptic currents in three subclasses of interneuron found in the CA1 region of the hippocampus. For both parvalbumin-positive and somatostatin-positive interneurons, the GluN2A subunit is expressed at glutamatergic synapses and contributes to the EPSC. In contrast, in cholecystokinin (CCK)-positive interneurons, the contribution of GluN2A to the EPSC is negligible. Furthermore, synaptic potentiation at glutamatergic synapses on CCK-positive interneurons does not require the activation of GluN2A-containing NMDARs but does rely on the activation of NMDARs containing GluN2B and GluN2D subunits.


Assuntos
Interneurônios , Receptores de N-Metil-D-Aspartato , Animais , Hipocampo/metabolismo , Interneurônios/metabolismo , Ratos , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo
14.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298875

RESUMO

Synaptic plasticity is an extensively studied cellular correlate of learning and memory in which NMDARs play a starring role. One of the most interesting features of NMDARs is their ability to act as a co-incident detector. It is unique amongst neurotransmitter receptors in this respect. Co-incident detection is possible because the opening of NMDARs requires membrane depolarisation and the binding of glutamate. Opening of NMDARs also requires a co-agonist. Although the dynamic regulation of glutamate and membrane depolarization have been well studied in coincident detection, the role of the co-agonist site is unexplored. It turns out that non-neuronal glial cells, astrocytes, regulate co-agonist availability, giving them the ability to influence synaptic plasticity. The unique morphology and spatial arrangement of astrocytes at the synaptic level affords them the capacity to sample and integrate information originating from unrelated synapses, regardless of any pre-synaptic and post-synaptic commonality. As astrocytes are classically considered slow responders, their influence at the synapse is widely recognized as modulatory. The aim herein is to reconsider the potential of astrocytes to participate directly in ongoing synaptic NMDAR activity and co-incident detection.


Assuntos
Astrócitos/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Ácido Glutâmico/metabolismo , Humanos , Plasticidade Neuronal/fisiologia , Sinapses/metabolismo
15.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281185

RESUMO

Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer's disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and studies on GE could provide unique insights into AD pathogenesis. Neurodegenerative diseases are typically late-onset disorders, but the underlying pathology may have already occurred long before the clinical symptoms emerge. Pathophysiology in the early phase of these diseases is understudied but critical for developing mechanism-based treatment. In AD, increased seizure susceptibility and silent epileptiform activity due to disrupted excitatory/inhibitory (E/I) balance has been identified much earlier than cognition deficit. Increased epileptiform activity is likely a main pathology in the early phase that directly contributes to impaired cognition. It is an enormous challenge to model the early phase of pathology with conventional AD mouse models due to the chronic disease course, let alone the complex interplay between subclinical nonconvulsive epileptiform activity, AD pathology, and cognition deficit. We have extensively studied GE, especially with gene mutations that affect the GABA pathway such as mutations in GABAA receptors and GABA transporter 1. We believe that some mouse models developed for studying GE and insights gained from GE could provide unique opportunity to understand AD. These include the pathology in early phase of AD, endoplasmic reticulum (ER) stress, and E/I imbalance as well as the contribution to cognitive deficit. In this review, we will focus on the overlapping mechanisms between GE and AD, the insights from mutations affecting GABAA receptors, and GABA transporter 1. We will detail mechanisms of E/I imbalance and the toxic epileptiform generation in AD, and the complex interplay between ER stress, impaired membrane protein trafficking, and synaptic physiology in both GE and AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Humanos , Camundongos , Receptores de GABA-A/metabolismo , Convulsões/genética , Convulsões/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Ácido gama-Aminobutírico/metabolismo
16.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206089

RESUMO

Amyloid-ß (Aß) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer's disease (AD). Whereas in AD, Aß is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aß aggregated species, soluble oligomers are suggested to be responsible for most of Aß's toxic effects. Aß oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aß deposition and facilitate neurodegeneration, resulting in an Aß-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aß induces on synaptic dysfunction and network disorganization.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Sinapses/genética , Transmissão Sináptica/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/efeitos adversos , Peptídeos beta-Amiloides/ultraestrutura , Proteínas Amiloidogênicas/efeitos adversos , Proteínas Amiloidogênicas/genética , Animais , Humanos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Multimerização Proteica/genética , Sinapses/metabolismo
17.
Science ; 373(6550): 77-81, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34210880

RESUMO

Brain postnatal development is characterized by critical periods of experience-dependent remodeling of neuronal circuits. Failure to end these periods results in neurodevelopmental disorders. The cellular processes defining critical-period timing remain unclear. Here, we show that in the mouse visual cortex, astrocytes control critical-period closure. We uncover the underlying pathway, which involves astrocytic regulation of the extracellular matrix, allowing interneuron maturation. Unconventional astrocyte connexin signaling hinders expression of extracellular matrix-degrading enzyme matrix metalloproteinase 9 (MMP9) through RhoA-guanosine triphosphatase activation. Thus, astrocytes not only influence the activity of single synapses but also are key elements in the experience-dependent wiring of brain circuits.


Assuntos
Astrócitos/fisiologia , Período Crítico Psicológico , Plasticidade Neuronal , Córtex Visual/crescimento & desenvolvimento , Animais , Astrócitos/metabolismo , Conexina 30/metabolismo , Ativação Enzimática , GTP Fosfo-Hidrolases/metabolismo , Interneurônios/metabolismo , Interneurônios/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sinapses/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
18.
Neuroscience ; 467: 188-200, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34215419

RESUMO

At the vertebrate neuromuscular junction (NMJ), presynaptic homeostatic potentiation (PHP) refers to the upregulation of neurotransmitter release via an increase in quantal content (QC) when the postsynaptic nicotinic acetylcholine receptors (nAChRs) are partially blocked. The mechanism of PHP has not been completely worked out. In particular, the identity of the presumed retrograde signal is still a mystery. We investigated the role of acid-sensing ion channels (ASICs) and extracellular protons in mediating PHP at the mouse NMJ. We found that blocking AISCs using benzamil, psalmotoxin-1 (PcTx1), or mambalgin-3 (Mamb3) prevented PHP. Likewise, extracellular acidification from pH 7.4 to 7.2 triggered a significant, reversable increase in QC and this increase could be prevented by PcTx1. Interestingly, an acidic saline (pH 7.2) also precluded the subsequent induction of PHP. Using immunofluorescence we observed ASIC2a and ASIC1 subunits at the NMJ. Our results indicate that protons and ASIC channels are involved in activating PHP at the mouse NMJ. We speculate that the partial blockade of nAChRs leads to a modest decrease in the pH of the synaptic cleft (∼0.2 pH units) and this activates ASIC channels on the presynaptic nerve terminal.


Assuntos
Junção Neuromuscular , Prótons , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Camundongos , Junção Neuromuscular/metabolismo , Terminações Pré-Sinápticas/metabolismo , Sinapses/metabolismo , Transmissão Sináptica
19.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208315

RESUMO

Onset and progression of Alzheimer's disease (AD) pathophysiology differs between brain regions. The neocortex, for example, is a brain region that is affected very early during AD. NMDA receptors (NMDARs) are involved in mediating amyloid beta (Aß) toxicity. NMDAR expression, on the other hand, can be affected by Aß. We tested whether the high vulnerability of neocortical neurons for Aß-toxicity may result from specific NMDAR expression profiles or from a particular regulation of NMDAR expression by Aß. Electrophysiological analyses suggested that pyramidal cells of 6-months-old wildtype mice express mostly GluN1/GluN2A NMDARs. While synaptic NMDAR-mediated currents are unaltered in 5xFAD mice, extrasynaptic NMDARs seem to contain GluN1/GluN2A and GluN1/GluN2A/GluN2B. We used conditional GluN1 and GluN2B knockout mice to investigate whether NMDARs contribute to Aß-toxicity. Spine number was decreased in pyramidal cells of 5xFAD mice and increased in neurons with 3-week virus-mediated Aß-overexpression. NMDARs were required for both Aß-mediated changes in spine number and functional synapses. Thus, our study gives novel insights into the Aß-mediated regulation of NMDAR expression and the role of NMDARs in Aß pathophysiology in the somatosensory cortex.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Espinhas Dendríticas/metabolismo , Neocórtex/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Doença de Alzheimer , Animais , Potenciais Pós-Sinápticos Excitadores , Camundongos Transgênicos , Subunidades Proteicas/metabolismo , Células Piramidais/metabolismo , Córtex Somatossensorial/metabolismo
20.
Biochemistry (Mosc) ; 86(7): 818-832, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34284706

RESUMO

This review focuses on new aspects of endocannabinoid functions and mechanisms of activity in central and peripheral synapses, different from the general viewpoint that endocannabinoids are retrograde signaling molecules, which inhibit neurotransmitter release by activating specific presynaptic endocannabinoid receptors CB1 and CB2. Biased agonism of the endogenous and synthetic cannabinoids as well as ability of the CB-receptors to couple not only with classical Gi-proteins, but also with Gs- and Gq-proteins and, moreover, with ß-arrestins (thereby triggering additional signaling pathways in synapses) are described here in detail. Examples of noncanonical tonic activity of endocannabinoids and their receptors and their role in synaptic function are also presented. The role of endocannabinoids in short-term and long-term potentiation of neurotransmitter release in central synapses and their facilitating effect on quantal size and other parameters of acetylcholine release in mammalian neuromuscular junctions are highlighted in this review. In conclusion, it is stated that the endocannabinoid system has a wider range of various multidirectional modulating effects (both potentiating and inhibiting) on neurotransmitter release than initially recognized. Re-evaluation of the functions of endocannabinoid system with consideration of its noncanonical features will lead to better understanding of its role in the normal and pathological functioning of the nervous system and other systems of the body, which has an enormous practical value.


Assuntos
Endocanabinoides/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Sinapses/metabolismo , Animais , Humanos , Transdução de Sinais , Sinapses/fisiologia , Transmissão Sináptica
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