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1.
Nat Commun ; 12(1): 3558, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117238

RESUMO

Hippocampal place cells contribute to mammalian spatial navigation and memory formation. Numerous models have been proposed to explain the location-specific firing of this cognitive representation, but the pattern of excitatory synaptic input leading to place firing is unknown, leaving no synaptic-scale explanation of place coding. Here we used resonant scanning two-photon microscopy to establish the pattern of synaptic glutamate input received by CA1 place cells in behaving mice. During traversals of the somatic place field, we found increased excitatory dendritic input, mainly arising from inputs with spatial tuning overlapping the somatic field, and functional clustering of this input along the dendrites over ~10 µm. These results implicate increases in total excitatory input and co-activation of anatomically clustered synaptic input in place firing. Since they largely inherit their fields from upstream synaptic partners with similar fields, many CA1 place cells appear to be part of multi-brain-region cell assemblies forming representations of specific locations.


Assuntos
Hipocampo/fisiologia , Células de Lugar/fisiologia , Memória Espacial/fisiologia , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Animais , Comportamento Animal , Região CA1 Hipocampal , Dendritos/fisiologia , Ácido Glutâmico , Hipocampo/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Plasticidade Neuronal/fisiologia , Neurotransmissores
2.
Cell Mol Life Sci ; 78(14): 5647-5663, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34128077

RESUMO

Inhibitory control is essential for the regulation of neuronal network activity, where excitatory and inhibitory synapses can act synergistically, reciprocally, and antagonistically. Sustained excitation-inhibition (E-I) balance, therefore, relies on the orchestrated adjustment of excitatory and inhibitory synaptic strength. While growing evidence indicates that the brain's extracellular matrix (ECM) is a crucial regulator of excitatory synapse plasticity, it remains unclear whether and how the ECM contributes to inhibitory control in neuronal networks. Here we studied the simultaneous changes in excitatory and inhibitory connectivity after ECM depletion. We demonstrate that the ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Quantification of synapses and super-resolution microscopy showed that depletion of the ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. The reduction of inhibitory synapse density is partially compensated by the homeostatically increasing synaptic strength via the reduction of presynaptic GABAB receptors, as indicated by patch-clamp measurements and GABAB receptor expression quantifications. However, both spiking and bursting activity in neuronal networks is increased after ECM depletion, as indicated by multi-electrode recordings. With computational modelling, we determined that ECM depletion reduces the inhibitory connectivity to an extent that the inhibitory synapse scaling does not fully compensate for the reduced inhibitory synapse density. Our results indicate that the brain's ECM preserves the balanced state of neuronal networks by supporting inhibitory control via inhibitory synapse stabilization, which expands the current understanding of brain activity regulation.


Assuntos
Potenciais Pós-Sinápticos Excitadores , Matriz Extracelular/fisiologia , Rede Nervosa/fisiologia , Plasticidade Neuronal , Neurônios/fisiologia , Sinapses/fisiologia , Transmissão Sináptica , Animais , Astrócitos/citologia , Astrócitos/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Receptores de GABA/metabolismo
3.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073798

RESUMO

Type IIa receptor tyrosine phosphatases (RPTPs) play pivotal roles in neuronal network formation. It is emerging that the interactions of RPTPs with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We highlight here the significance of these interactions in axon regeneration and synaptogenesis. For example, PTPσ, a member of type IIa RPTPs, on axon terminals is monomerized and activated by the extracellular CS deposited in neural injuries, dephosphorylates cortactin, disrupts autophagy flux, and consequently inhibits axon regeneration. In contrast, HS induces PTPσ oligomerization, suppresses PTPσ phosphatase activity, and promotes axon regeneration. PTPσ also serves as an organizer of excitatory synapses. PTPσ and neurexin bind one another on presynapses and further bind to postsynaptic leucine-rich repeat transmembrane protein 4 (LRRTM4). Neurexin is now known as a heparan sulfate proteoglycan (HSPG), and its HS is essential for the binding between these three molecules. Another HSPG, glypican 4, binds to presynaptic PTPσ and postsynaptic LRRTM4 in an HS-dependent manner. Type IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic binding to a variety of postsynaptic partners. We also discuss the important issue of possible mechanisms coordinating axon extension and synapse formation.


Assuntos
Axônios/metabolismo , Regeneração Nervosa , Polissacarídeos/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Sinapses/metabolismo , Animais , Axônios/fisiologia , Humanos , Polissacarídeos/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/metabolismo , Sinapses/fisiologia
4.
Nat Commun ; 12(1): 3351, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099691

RESUMO

Incorporating neuromorphic electronics in bioelectronic interfaces can provide intelligent responsiveness to environments. However, the signal mismatch between the environmental stimuli and driving amplitude in neuromorphic devices has limited the functional versatility and energy sustainability. Here we demonstrate multifunctional, self-sustained neuromorphic interfaces by achieving signal matching at the biological level. The advances rely on the unique properties of microbially produced protein nanowires, which enable both bio-amplitude (e.g., <100 mV) signal processing and energy harvesting from ambient humidity. Integrating protein nanowire-based sensors, energy devices and memristors of bio-amplitude functions yields flexible, self-powered neuromorphic interfaces that can intelligently interpret biologically relevant stimuli for smart responses. These features, coupled with the fact that protein nanowires are a green biomaterial of potential diverse functionalities, take the interfaces a step closer to biological integration.


Assuntos
Nanotecnologia/instrumentação , Nanotecnologia/métodos , Nanofios , Materiais Biocompatíveis , Eletrônica/instrumentação , Redes Neurais de Computação , Proteínas , Sinapses/fisiologia
5.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946908

RESUMO

Alterations of zinc homeostasis have long been implicated in Parkinson's disease (PD). Zinc plays a complex role as both deficiency and excess of intracellular zinc levels have been incriminated in the pathophysiology of the disease. Besides its role in multiple cellular functions, Zn2+ also acts as a synaptic transmitter in the brain. In the forebrain, subset of glutamatergic neurons, namely cortical neurons projecting to the striatum, use Zn2+ as a messenger alongside glutamate. Overactivation of the cortico-striatal glutamatergic system is a key feature contributing to the development of PD symptoms and dopaminergic neurotoxicity. Here, we will cover recent evidence implicating synaptic Zn2+ in the pathophysiology of PD and discuss its potential mechanisms of actions. Emphasis will be placed on the functional interaction between Zn2+ and glutamatergic NMDA receptors, the most extensively studied synaptic target of Zn2+.


Assuntos
Doença de Parkinson/fisiopatologia , Sinapses/fisiologia , Zinco/fisiologia , Animais , Gânglios da Base/fisiopatologia , Proteínas de Transporte de Cátions/deficiência , Córtex Cerebral/fisiopatologia , Quelantes/farmacologia , Quelantes/uso terapêutico , Corpo Estriado/fisiopatologia , Feminino , Homeostase , Humanos , Líquido Intracelular/metabolismo , Masculino , Camundongos , Camundongos Knockout , Degeneração Neural/fisiopatologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Transmissão Sináptica/fisiologia
6.
Nat Commun ; 12(1): 2912, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006874

RESUMO

The hippocampal mossy fiber synapse is a key synapse of the trisynaptic circuit. Post-tetanic potentiation (PTP) is the most powerful form of plasticity at this synaptic connection. It is widely believed that mossy fiber PTP is an entirely presynaptic phenomenon, implying that PTP induction is input-specific, and requires neither activity of multiple inputs nor stimulation of postsynaptic neurons. To directly test cooperativity and associativity, we made paired recordings between single mossy fiber terminals and postsynaptic CA3 pyramidal neurons in rat brain slices. By stimulating non-overlapping mossy fiber inputs converging onto single CA3 neurons, we confirm that PTP is input-specific and non-cooperative. Unexpectedly, mossy fiber PTP exhibits anti-associative induction properties. EPSCs show only minimal PTP after combined pre- and postsynaptic high-frequency stimulation with intact postsynaptic Ca2+ signaling, but marked PTP in the absence of postsynaptic spiking and after suppression of postsynaptic Ca2+ signaling (10 mM EGTA). PTP is largely recovered by inhibitors of voltage-gated R- and L-type Ca2+ channels, group II mGluRs, and vacuolar-type H+-ATPase, suggesting the involvement of retrograde vesicular glutamate signaling. Transsynaptic regulation of PTP extends the repertoire of synaptic computations, implementing a brake on mossy fiber detonation and a "smart teacher" function of hippocampal mossy fiber synapses.


Assuntos
Fibras Musgosas Hipocampais/fisiologia , Plasticidade Neuronal/fisiologia , Terminações Pré-Sinápticas/fisiologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Animais , Células Cultivadas , Estimulação Elétrica , Potenciais Evocados/fisiologia , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Masculino , Técnicas de Patch-Clamp , Ratos , Potenciais Sinápticos/fisiologia
7.
Nat Commun ; 12(1): 2881, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001888

RESUMO

The mechanisms by which sleep benefits learning and memory remain unclear. Sleep may further strengthen the synapses potentiated by learning or promote broad synaptic weakening while protecting the newly potentiated synapses. We tested these ideas by combining a motor task whose consolidation is sleep-dependent, a marker of synaptic AMPA receptor plasticity, and repeated two-photon imaging to track hundreds of spines in vivo with single spine resolution. In mouse motor cortex, sleep leads to an overall net decrease in spine-surface GluA1-containing AMPA receptors, both before and after learning. Molecular changes in single spines during post-learning sleep are correlated with changes in performance after sleep. The spines in which learning leads to the largest increase in GluA1 expression have a relative advantage after post-learning sleep compared to sleep deprivation, because sleep weakens all remaining spines. These results are obtained in adult mice, showing that sleep-dependent synaptic down-selection also benefits the mature brain.


Assuntos
Espinhas Dendríticas/metabolismo , Aprendizagem/fisiologia , Córtex Motor/fisiologia , Receptores de AMPA/metabolismo , Sono/fisiologia , Animais , Feminino , Masculino , Memória/fisiologia , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Atividade Motora/fisiologia , Córtex Motor/citologia , Córtex Motor/metabolismo , Privação do Sono/fisiopatologia , Sinapses/metabolismo , Sinapses/fisiologia
8.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925434

RESUMO

The investigation of synaptic functions remains one of the most fascinating challenges in the field of neuroscience and a large number of experimental methods have been tuned to dissect the mechanisms taking part in the neurotransmission process. Furthermore, the understanding of the insights of neurological disorders originating from alterations in neurotransmission often requires the development of (i) animal models of pathologies, (ii) invasive tools and (iii) targeted pharmacological approaches. In the last decades, additional tools to explore neurological diseases have been provided to the scientific community. A wide range of computational models in fact have been developed to explore the alterations of the mechanisms involved in neurotransmission following the emergence of neurological pathologies. Here, we review some of the advancements in the development of computational methods employed to investigate neuronal circuits with a particular focus on the application to the most diffuse neurological disorders.


Assuntos
Modelos Neurológicos , Doenças do Sistema Nervoso/etiologia , Transmissão Sináptica/fisiologia , Doença de Alzheimer/etiologia , Animais , Dendritos/fisiologia , Epilepsia/etiologia , Humanos , Doenças do Sistema Nervoso/fisiopatologia , Doença de Parkinson/etiologia , Esquizofrenia/etiologia , Sinapses/fisiologia
9.
Nature ; 592(7854): 414-420, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33828296

RESUMO

Critical periods-brief intervals during which neural circuits can be modified by activity-are necessary for proper neural circuit assembly. Extended critical periods are associated with neurodevelopmental disorders; however, the mechanisms that ensure timely critical period closure remain poorly understood1,2. Here we define a critical period in a developing Drosophila motor circuit and identify astrocytes as essential for proper critical period termination. During the critical period, changes in activity regulate dendrite length, complexity and connectivity of motor neurons. Astrocytes invaded the neuropil just before critical period closure3, and astrocyte ablation prolonged the critical period. Finally, we used a genetic screen to identify astrocyte-motor neuron signalling pathways that close the critical period, including Neuroligin-Neurexin signalling. Reduced signalling destabilized dendritic microtubules, increased dendrite dynamicity and impaired locomotor behaviour, underscoring the importance of critical period closure. Previous work defined astroglia as regulators of plasticity at individual synapses4; we show here that astrocytes also regulate motor circuit critical period closure to ensure proper locomotor behaviour.


Assuntos
Astrócitos/fisiologia , Período Crítico Psicológico , Drosophila melanogaster/citologia , Drosophila melanogaster/fisiologia , Vias Eferentes/fisiologia , Neurônios Motores/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Dendritos/fisiologia , Feminino , Locomoção/fisiologia , Masculino , Microtúbulos/metabolismo , Neurópilo/fisiologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Sinapses/fisiologia , Fatores de Tempo
10.
Science ; 372(6539)2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33859005

RESUMO

Protocadherin-19 (PCDH19) mutations cause early-onset seizures and cognitive impairment. The PCDH19 gene is on the X-chromosome. Unlike most X-linked disorders, PCDH19 mutations affect heterozygous females (PCDH19HET♀ ) but not hemizygous males (PCDH19HEMI♂ ); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. Pcdh19HET♀ but not Pcdh19HEMI♂ mice show impaired mossy fiber synaptic structure and physiology. Consistently, Pcdh19HET♀ but not Pcdh19HEMI♂ mice exhibit reduced pattern completion and separation abilities, which require mossy fiber synaptic function. Furthermore, PCDH19 appears to interact with N-cadherin at mossy fiber synapses. In Pcdh19HET♀ conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin-dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues Pcdh19HET♀ phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype.


Assuntos
Caderinas/metabolismo , Disfunção Cognitiva/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Fibras Musgosas Hipocampais/fisiopatologia , Sinapses/fisiologia , Animais , Região CA3 Hipocampal/fisiopatologia , Região CA3 Hipocampal/ultraestrutura , Caderinas/genética , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Potenciação de Longa Duração , Masculino , Camundongos , Fibras Musgosas Hipocampais/ultraestrutura , Mutação , Caracteres Sexuais , Sinapses/ultraestrutura , beta Catenina/metabolismo
11.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800863

RESUMO

The ability to sense and move within an environment are complex functions necessary for the survival of nearly all species. The spinal cord is both the initial entry site for peripheral information and the final output site for motor response, placing spinal circuits as paramount in mediating sensory responses and coordinating movement. This is partly accomplished through the activation of complex spinal microcircuits that gate afferent signals to filter extraneous stimuli from various sensory modalities and determine which signals are transmitted to higher order structures in the CNS and to spinal motor pathways. A mechanistic understanding of how inhibitory interneurons are organized and employed within the spinal cord will provide potential access points for therapeutics targeting inhibitory deficits underlying various pathologies including sensory and movement disorders. Recent studies using transgenic manipulations, neurochemical profiling, and single-cell transcriptomics have identified distinct populations of inhibitory interneurons which express an array of genetic and/or neurochemical markers that constitute functional microcircuits. In this review, we provide an overview of identified neural components that make up inhibitory microcircuits within the dorsal and ventral spinal cord and highlight the importance of inhibitory control of sensorimotor pathways at the spinal level.


Assuntos
Vias Aferentes/fisiologia , Interneurônios/fisiologia , Movimento/fisiologia , Inibição Neural/fisiologia , Sensação/fisiologia , Filtro Sensorial/fisiologia , Medula Espinal/citologia , Animais , Células do Corno Anterior/química , Células do Corno Anterior/classificação , Células do Corno Anterior/fisiologia , Humanos , Interneurônios/química , Interneurônios/classificação , Modelos Neurológicos , Neurônios Motores/fisiologia , Transtornos dos Movimentos/fisiopatologia , Fibras Nervosas/fisiologia , Proteínas do Tecido Nervoso/análise , Neuropeptídeos/análise , Células do Corno Posterior/química , Células do Corno Posterior/classificação , Transtornos das Sensações/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Medula Espinal/fisiologia , Sinapses/fisiologia
12.
Nat Commun ; 12(1): 2030, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795678

RESUMO

Microglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer's disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer's disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.


Assuntos
Doença de Alzheimer/genética , Modelos Animais de Doenças , Microglia/metabolismo , Plasticidade Neuronal/genética , Receptores Imunológicos/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Animais , Células Cultivadas , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/citologia , Receptores Imunológicos/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia
13.
Neuron ; 109(8): 1333-1349.e6, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33770504

RESUMO

To establish functional neural circuits in the brain, synaptic connections are refined by neural activity during development, where active connections are maintained and inactive ones are eliminated. However, the molecular signals that regulate synapse refinement remain to be elucidated. When we inactivate a subset of neurons in the mouse cingulate cortex, their callosal connections are eliminated through activity-dependent competition. Using this system, we identify JAK2 tyrosine kinase as a key regulator of inactive synapse elimination. We show that JAK2 is necessary and sufficient for elimination of inactive connections; JAK2 is activated at inactive synapses in response to signals from other active synapses; STAT1, a substrate of JAK2, mediates inactive synapse elimination; JAK2 signaling is critical for physiological refinement of synapses during normal development; and JAK2 regulates synapse refinement in multiple brain regions. We propose that JAK2 is an activity-dependent switch that serves as a determinant of inactive synapse elimination.


Assuntos
Giro do Cíngulo/fisiologia , Janus Quinase 2/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Giro do Cíngulo/metabolismo , Camundongos , Neurônios/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/fisiologia , Sinapses/metabolismo
14.
Adv Pharmacol ; 90: 173-216, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33706932

RESUMO

Beyond their rapid rewarding effects, drugs of abuse can durably alter an individual's response to their environment as illustrated by the compulsive drug seeking and risk of relapse triggered by drug-associated stimuli. The persistence of these associations even long after cessation of drug use demonstrates the enduring mark left by drugs on brain reward circuits. However, within these circuits, neuronal populations are differently affected by drug exposure and growing evidence indicates that relatively small subsets of neurons might be involved in the encoding and expression of drug-mediated associations. The identification of sparse neuronal populations recruited in response to drug exposure has benefited greatly from the study of immediate early genes (IEGs) whose induction is critical in initiating plasticity programs in recently activated neurons. In particular, the development of technologies to manipulate IEG-expressing cells has been fundamental to implicate broadly distributed neuronal ensembles coincidently activated by either drugs or drug-associated stimuli and to then causally establish their involvement in drug responses. In this review, we summarize the literature regarding IEG regulation in different learning paradigms and addiction models to highlight their role as a marker of activity and plasticity. As the exploration of neuronal ensembles in addiction improves our understanding of drug-associated memory encoding, it also raises several questions regarding the cellular and molecular characteristics of these discrete neuronal populations as they become incorporated in drug-associated neuronal ensembles. We review recent efforts towards this goal and discuss how they will offer a more comprehensive understanding of addiction pathophysiology.


Assuntos
Comportamento Aditivo/genética , Genes Precoces , Neurônios/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Humanos , Plasticidade Neuronal , Sinapses/fisiologia
15.
Nat Commun ; 12(1): 1398, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658519

RESUMO

We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived induced pluripotent stem cells (iPSCs). Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits. We further generated a knock-in mouse line harboring the same patient mutation in the Disc1 gene. Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain, and social and cognitive behavioral deficits. Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. Our study shows that patient-derived isogenic iPSC and humanized mouse disease models are integral and complementary for translational studies with a better understanding of underlying molecular mechanisms.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Inibidores da Fosfodiesterase 4/farmacologia , Esquizofrenia/genética , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/fisiologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos Mutantes , Mutação , Neurônios/efeitos dos fármacos , Rolipram/farmacologia , Esquizofrenia/patologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
16.
Nat Commun ; 12(1): 1903, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771994

RESUMO

Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer's disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.


Assuntos
Doença de Alzheimer/genética , Proteínas do Citoesqueleto/genética , Transtornos da Memória/genética , MicroRNAs/genética , Sinapses/metabolismo , Quinases Associadas a rho/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/fisiologia , Fosforilação , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sinapses/fisiologia , Quinases Associadas a rho/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
17.
Nat Commun ; 12(1): 1932, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771998

RESUMO

The physical distance between presynaptic Ca2+ channels and the Ca2+ sensors triggering the release of neurotransmitter-containing vesicles regulates short-term plasticity (STP). While STP is highly diversified across synapse types, the computational and behavioral relevance of this diversity remains unclear. In the Drosophila brain, at nanoscale level, we can distinguish distinct coupling distances between Ca2+ channels and the (m)unc13 family priming factors, Unc13A and Unc13B. Importantly, coupling distance defines release components with distinct STP characteristics. Here, we show that while Unc13A and Unc13B both contribute to synaptic signalling, they play distinct roles in neural decoding of olfactory information at excitatory projection neuron (ePN) output synapses. Unc13A clusters closer to Ca2+ channels than Unc13B, specifically promoting fast phasic signal transfer. Reduction of Unc13A in ePNs attenuates responses to both aversive and appetitive stimuli, while reduction of Unc13B provokes a general shift towards appetitive values. Collectively, we provide direct genetic evidence that release components of distinct nanoscopic coupling distances differentially control STP to play distinct roles in neural decoding of sensory information.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Animais Geneticamente Modificados , Comportamento Apetitivo/fisiologia , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Feminino , Interneurônios/metabolismo , Interneurônios/fisiologia , Proteínas de Membrana/genética , Microscopia Confocal , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferência de RNA , Sinapses/metabolismo , Transmissão Sináptica/genética , Vesículas Sinápticas/metabolismo
18.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672634

RESUMO

Cannabis has long been used for its medicinal and psychoactive properties. With the relatively new adoption of formal medicinal cannabis regulations worldwide, the study of cannabinoids, both endogenous and exogenous, has similarly flourished in more recent decades. In particular, research investigating the role of cannabinoids in regeneration and neurodevelopment has yielded promising results in vertebrate models. However, regeneration-competent vertebrates are few, whereas a myriad of invertebrate species have been established as superb models for regeneration. As such, this review aims to provide a comprehensive summary of the endocannabinoid system, with a focus on current advances in the area of endocannabinoid system contributions to invertebrate neurodevelopment and regeneration.


Assuntos
Endocanabinoides/metabolismo , Invertebrados/fisiologia , Sistema Nervoso/crescimento & desenvolvimento , Regeneração , Animais , Humanos , Modelos Biológicos , Sinapses/fisiologia
19.
J Neurosci ; 41(11): 2318-2328, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33627325

RESUMO

Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional features of neuromodulatory transmission remains challenging because of limitations of available monitoring tools. Recently developed genetically encoded neuromodulatory transmitter sensors, when combined with superresolution and/or deconvolution microscopy, allow the first visualization of neuromodulatory transmission with nanoscale or microscale spatiotemporal resolution. In vitro and in vivo experiments have validated several high-performing sensors to have the qualities necessary for demarcating fundamental synaptic properties of neuromodulatory transmission, and initial analysis has unveiled unexpected fine control and precision of neuromodulation. These new findings underscore the importance of synaptic dynamics in synapse-, subcellular-, and circuit-specific neuromodulation, as well as the prospect of genetically encoded transmitter sensors in expanding our knowledge of various behaviors and diseases, including Alzheimer's disease, sleeping disorders, tumorigenesis, and many others.


Assuntos
Acetilcolina/fisiologia , Monoaminas Biogênicas/fisiologia , Comunicação Celular/genética , Neurônios/fisiologia , Neurotransmissores/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Humanos
20.
Neural Netw ; 138: 126-139, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33639581

RESUMO

In spiking neural P (SN P) systems, neurons are interconnected by means of synapses, and they use spikes to communicate with each other. However, in biology, the complex structure of dendritic tree is also an important part in the communication scheme between neurons since these structures are linked to advanced neural process such as learning and memory formation. In this work, we present a new variant of the SN P systems inspired by diverse dendrite and axon phenomena such as dendritic feedback, dendritic trunk, dendritic delays and axonal delays, respectively. This new variant is referred to as a spiking neural P system with dendritic and axonal computation (DACSN P system). Specifically, we include experimentally proven biological features in the current SN P systems to reduce the computational complexity of the soma by providing it with stable firing patterns through dendritic delays, dendritic feedback and axonal delays. As a consequence, the proposed DACSN P systems use the minimum number of synapses and neurons with simple and homogeneous standard spiking rules. Here, we study the computational capabilities of a DACSN P system. In particular, we prove that DACSN P systems with dendritic and axonal behavior are universal as both number-accepting/generating devices. In addition, we constructed a small universal SN P system using 39 neurons with standard spiking rules to compute any Turing computable function.


Assuntos
Retroalimentação , Modelos Neurológicos , Redes Neurais de Computação , Sinapses/fisiologia , Potenciais de Ação , Axônios/fisiologia , Dendritos/fisiologia , Humanos , Tempo de Reação
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