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1.
bioRxiv ; 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37986838

RESUMO

Genetically encoded calcium indicators (GECIs) such as GCaMP are invaluable tools in neuroscience to monitor neuronal activity using optical imaging. The viral transduction of GECIs is commonly used to target expression to specific brain regions, can be conveniently used with any mouse strain of interest without the need for prior crossing with a GECI mouse line and avoids potential hazards due to the chronic expression of GECIs during development. A key requirement for monitoring neuronal activity with an indicator is that the indicator itself minimally affects activity. Here, using common adeno-associated viral (AAV) transduction procedures, we describe spatially confined aberrant Ca2+ micro-waves slowly travelling through the hippocampus following expression of GCaMP6, GCaMP7 or R-CaMP1.07 driven by the synapsin promoter with AAV-dependent gene transfer, in a titre-dependent fashion. Ca2+ micro-waves developed in hippocampal CA1 and CA3, but not dentate gyrus (DG) nor neocortex, were typically first observed at 4 weeks after viral transduction, and persisted up to at least 8 weeks. The phenomenon was robust, observed across laboratories with various experimenters and setups. Our results indicate that aberrant hippocampal Ca2+ micro-waves depend on the promoter and viral titre of the GECI, density of expression as well as the targeted brain region. We used an alternative viral transduction method of GCaMP which avoids this artifact. The results show that commonly used Ca2+-indicator AAV transduction procedures can produce artefactual Ca2+ responses. Our aim is to raise awareness in the field of these artefactual transduction-induced Ca2+ micro-waves and we provide a potential solution.

2.
Neurobiol Dis ; 182: 106126, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37086756

RESUMO

Intraneuronal aggregates of the microtubule binding protein Tau are a hallmark of different neurodegenerative diseases including Alzheimer's disease (AD). In these aggregates, Tau is modified by posttranslational modifications such as phosphorylation as well as by proteolytic cleavage. Here we identify a novel Tau cleavage site at aspartate 65 (D65) that is specific for caspase-2. In addition, we show that the previously described cleavage site at D421 is also efficiently processed by caspase-2, and both sites are cleaved in human brain samples. Caspase-2-generated Tau fragments show increased aggregation potential in vitro, but do not accumulate in vivo after AAV-mediated overexpression in mouse hippocampus. Interestingly, we observe that steady-state protein levels of caspase-2 generated Tau fragments are low in our in vivo model despite strong RNA expression, suggesting efficient clearance. Consistent with this hypothesis, we find that caspase-2 cleavage significantly improves the recognition of Tau by the ubiquitin E3 ligase CHIP, leading to increased ubiquitination and faster degradation of Tau fragments. Taken together our data thus suggest that CHIP-induced ubiquitination is of particular importance for the clearance of caspase-2 generated Tau fragments in vitro and in vivo.


Assuntos
Caspase 2 , Proteínas tau , Humanos , Masculino , Feminino , Animais , Camundongos , Modelos Animais de Doenças , Proteínas tau/química , Proteínas tau/genética , Proteínas tau/metabolismo , Caspase 2/metabolismo , Encéfalo/metabolismo , Imunoprecipitação da Cromatina , Ubiquitinação
3.
Elife ; 122023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36749020

RESUMO

Microglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglial motility and significance for synapse stability, especially in the hippocampus during adulthood, remain widely unresolved. Here, we investigated the effect of neuronal activity on microglial motility and the implications for the formation and survival of dendritic spines on hippocampal CA1 neurons in vivo. We used repetitive two-photon in vivo imaging in the hippocampus of awake and anesthetized mice to simultaneously study the motility of microglia and their interaction with dendritic spines. We found that CA3 to CA1 input is sufficient to modulate microglial process motility. Simultaneously, more dendritic spines emerged in mice after awake compared to anesthetized imaging. Interestingly, the rate of microglial contacts with individual dendritic spines and dendrites was associated with the stability, removal, and emergence of dendritic spines. These results suggest that microglia might sense neuronal activity via neurotransmitter release and actively participate in synaptic rewiring of the hippocampal neural network during adulthood. Further, this study has profound relevance for hippocampal learning and memory processes.


Assuntos
Espinhas Dendríticas , Microglia , Camundongos , Animais , Microglia/fisiologia , Espinhas Dendríticas/fisiologia , Vigília , Hipocampo/fisiologia , Neurônios , Plasticidade Neuronal/fisiologia
4.
Nat Commun ; 13(1): 7525, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36473867

RESUMO

We developed a family of genetically encoded serotonin (5-HT) sensors (sDarken) on the basis of the native 5-HT1A receptor and circularly permuted GFP. sDarken 5-HT sensors are bright in the unbound state and diminish their fluorescence upon binding of 5-HT. Sensor variants with different affinities for serotonin were engineered to increase the versatility in imaging of serotonin dynamics. Experiments in vitro and in vivo showed the feasibility of imaging serotonin dynamics with high temporal and spatial resolution. As demonstrated here, the designed sensors show excellent membrane expression, have high specificity and a superior signal-to-noise ratio, detect the endogenous release of serotonin and are suitable for two-photon in vivo imaging.


Assuntos
Serotonina
5.
J Neurosci ; 42(45): 8488-8497, 2022 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-36351828

RESUMO

Super-resolution fluorescence microscopy holds tremendous potential for discovery in neuroscience. Much of the molecular machinery and anatomic specializations that give rise to the unique and bewildering electrochemical activity of neurons are nanoscale by design, ranging somewhere between 1 nm and 1 µm. It is at this scale where most of the unknown and exciting action is and where cell biologists flock to in their dreams, but it was off limits for light microscopy until recently. While the optical principles of super-resolution microscopy are firmly established by now, the technology continues to advance rapidly in many crucial areas, enhancing its performance and reliability, and making it more accessible and user-friendly, which is sorely needed. Indeed, super-resolution microscopy techniques are nowadays widely used for visualizing immunolabeled protein distributions in fixed or living cells. However, a great potential of super-resolution microscopy for neuroscience lies in shining light on the nanoscale structures and biochemical activities in live-tissue settings, which should be developed and harnessed much more fully. In this review, we will present several vivid examples based on STED and RESOLFT super-resolution microscopy, illustrating the possibilities and challenges of nano-imaging in vivo to pique the interest of tech-developers and neurobiologists alike. We will cover recent technical progress that is facilitating in vivo applications, and share new biological insights into the nanoscale mechanisms of cellular communication between neurons and glia.


Assuntos
Neurônios , Reprodutibilidade dos Testes , Microscopia de Fluorescência/métodos
7.
Neuron ; 110(10): 1606-1608, 2022 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-35588712

RESUMO

A balanced and fine-tuned ratio of neuronal excitation and inhibition is a prerequisite for information processing. In this issue of Neuron, He et al. (2022) reveal a causal link between reduced input to local somatostatin-expressing, MeCP2-negative O-LM interneurons in CA1 and long-term memory impairment in a mouse model of Rett syndrome.


Assuntos
Células Piramidais , Síndrome de Rett , Animais , Hipocampo , Interneurônios/fisiologia , Camundongos , Células Piramidais/fisiologia
8.
Mol Psychiatry ; 26(7): 3489-3501, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33837272

RESUMO

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.


Assuntos
Córtex Pré-Frontal , Esquizofrenia , Animais , Complemento C4 , Interneurônios/metabolismo , Camundongos , Parvalbuminas/metabolismo , Fenótipo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética
9.
J Neurochem ; 157(6): 2128-2144, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33583024

RESUMO

Neuronal network dysfunction is a hallmark of Alzheimer's disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in transgenic McGill-R-Thy1-APP rats (APPtg) at the beginning of extracellular amyloid beta (Aß) deposition. We established two-photon Ca2+ -imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. We did neither observe changes in synaptic inhibition, nor in excitation. Our data support the view that increased intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of Aß-deposition and disease progression.


Assuntos
Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Feminino , Hipocampo/patologia , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Transgênicos
11.
Cell Death Differ ; 27(12): 3354-3373, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32641776

RESUMO

Dendritic spines are postsynaptic domains that shape structural and functional properties of neurons. Upon neuronal activity, Ca2+ transients trigger signaling cascades that determine the plastic remodeling of dendritic spines, which modulate learning and memory. Here, we study in mice the role of the intracellular Ca2+ channel Ryanodine Receptor 2 (RyR2) in synaptic plasticity and memory formation. We demonstrate that loss of RyR2 in pyramidal neurons of the hippocampus impairs maintenance and activity-evoked structural plasticity of dendritic spines during memory acquisition. Furthermore, post-developmental deletion of RyR2 causes loss of excitatory synapses, dendritic sparsification, overcompensatory excitability, network hyperactivity and disruption of spatially tuned place cells. Altogether, our data underpin RyR2 as a link between spine remodeling, circuitry dysfunction and memory acquisition, which closely resemble pathological mechanisms observed in neurodegenerative disorders.


Assuntos
Espinhas Dendríticas/fisiologia , Hipocampo/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Sinapses/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Células Piramidais/metabolismo
12.
Nat Neurosci ; 23(8): 952-958, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514139

RESUMO

In Alzheimer's disease (AD), hippocampus-dependent memories underlie an extensive decline. The neuronal ensemble encoding a memory, termed engram, is partially recapitulated during memory recall. Artificial activation of an engram can restore memory in a mouse model of early AD, but its fate and the factors that render the engram nonfunctional are yet to be revealed. Here, we used repeated two-photon in vivo imaging to analyze fosGFP transgenic mice (which express enhanced GFP under the Fos promoter) performing a hippocampus-dependent memory task. We found that partial reactivation of the CA1 engram during recall is preserved under AD-like conditions. However, we identified a novelty-like ensemble that interfered with the engram and thus compromised recall. Mimicking a novelty-like ensemble in healthy mice was sufficient to affect memory recall. In turn, reducing the novelty-like signal rescued the recall impairment under AD-like conditions. These findings suggest a novel mechanistic process that contributes to the deterioration of memories in AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Hipocampo/fisiologia , Rememoração Mental/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Optogenética , Proteínas Proto-Oncogênicas c-fos/genética
13.
PLoS Biol ; 17(8): e3000374, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393866

RESUMO

A deep understanding of how regulation of the multiple levels of gene expression in mammalian tissues give rise to complex phenotypes has been impeded by cellular diversity. A handful of techniques were developed to tag-select nucleic acids of interest in specific cell types, thereby enabling their capture. We expanded this strategy by developing the Tagger knock-in mouse line bearing a quad-cistronic transgene combining enrichment tools for nuclei, nascent RNA, translating mRNA, and mature microRNA (miRNA). We demonstrate that Tagger can capture the desired nucleic acids, enabling multiple omics approaches to be applied to specific cell types in vivo using a single transgenic mouse line.


Assuntos
Perfilação da Expressão Gênica/métodos , Ácidos Nucleicos/isolamento & purificação , Sequenciamento Completo do Genoma/métodos , Animais , Clonagem Molecular/métodos , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Técnicas de Introdução de Genes , Genômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/genética , MicroRNAs/genética , Proteômica/métodos , RNA Mensageiro/genética , Transcriptoma/genética , Transgenes/genética
14.
Brain Res ; 1707: 216-226, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30503351

RESUMO

Alzheimer's disease (AD) is characterized by the classical hallmarks of Aß-deposition and tau-pathology that are thought to ultimately lead to synapse and neuron loss. Although long known, neuroinflammation has recently attracted a substantial amount of attention by researchers due to genome wide association studies (GWAS) that identified microglia associated genes to be correlated with sporadic AD. Besides that, cholinergic degeneration and gamma-aminobutyric acid (GABA) abnormalities have been identified in the brains of AD patients already decades ago, but have not received much attention over the last ten years. Recently, the neuronal network dysfunction hypothesis has revived interest in how impairments of neuronal communication at the network level lead to epileptiform activity and disrupted oscillations observed in the brains of AD patients and mouse models. Thereby, deficits in neuronal networks involved in learning and memory might ultimately cause memory impairments. In this context, an imbalance between excitation and inhibition has been hypothesized to contribute to neuronal network dysfunction. Here, disturbances of cholinergic and GABAergic transmission might play a crucial role. In this review, we will focus on GABAergic dysfunction in AD and mouse models of AD and how those might relate to neuronal network aberration and memory impairment.


Assuntos
Doença de Alzheimer/fisiopatologia , Neurônios GABAérgicos/metabolismo , Rede Nervosa/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Memória/fisiologia , Transtornos da Memória/patologia , Degeneração Neural/patologia , Neurônios/metabolismo , Ácido gama-Aminobutírico/metabolismo , Proteínas tau/metabolismo
15.
Elife ; 72018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29932052

RESUMO

Rewiring neural circuits by the formation and elimination of synapses is thought to be a key cellular mechanism of learning and memory in the mammalian brain. Dendritic spines are the postsynaptic structural component of excitatory synapses, and their experience-dependent plasticity has been extensively studied in mouse superficial cortex using two-photon microscopy in vivo. By contrast, very little is known about spine plasticity in the hippocampus, which is the archetypical memory center of the brain, mostly because it is difficult to visualize dendritic spines in this deeply embedded structure with sufficient spatial resolution. We developed chronic 2P-STED microscopy in mouse hippocampus, using a 'hippocampal window' based on resection of cortical tissue and a long working distance objective for optical access. We observed a two-fold higher spine density than previous studies and measured a spine turnover of ~40% within 4 days, which depended on spine size. We thus provide direct evidence for a high level of structural rewiring of synaptic circuits and new insights into the structure-dynamics relationship of hippocampal spines. Having established chronic super-resolution microscopy in the hippocampus in vivo, our study enables longitudinal and correlative analyses of nanoscale neuroanatomical structures with genetic, molecular and behavioral experiments.


Assuntos
Espinhas Dendríticas/ultraestrutura , Hipocampo/ultraestrutura , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Imagem Molecular/métodos , Rede Nervosa/ultraestrutura , Células Piramidais/ultraestrutura , Sinapses/ultraestrutura , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Córtex Cerebral/cirurgia , Espinhas Dendríticas/fisiologia , Feminino , Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/anatomia & histologia , Hipocampo/fisiologia , Processamento de Imagem Assistida por Computador/estatística & dados numéricos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica/instrumentação , Imagem Molecular/instrumentação , Rede Nervosa/anatomia & histologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia , Sinapses/fisiologia
16.
J Exp Med ; 215(6): 1649-1663, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29724785

RESUMO

Astrocytic hyperactivity is an important contributor to neuronal-glial network dysfunction in Alzheimer's disease (AD). We have previously shown that astrocyte hyperactivity is mediated by signaling through the P2Y1 purinoreceptor (P2Y1R) pathway. Using the APPPS1 mouse model of AD, we here find that chronic intracerebroventricular infusion of P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, as measured by in vivo two-photon microscopy, augments structural synaptic integrity, and preserves hippocampal long-term potentiation. These effects occur independently from ß-amyloid metabolism or plaque burden but are associated with a higher morphological complexity of periplaque reactive astrocytes, as well as reduced dystrophic neurite burden and greater plaque compaction. Importantly, APPPS1 mice chronically treated with P2Y1R antagonists, as well as APPPS1 mice carrying an astrocyte-specific genetic deletion (Ip3r2-/-) of signaling pathways downstream of P2Y1R activation, are protected from the decline of spatial learning and memory. In summary, our study establishes the restoration of network homoeostasis by P2Y1R inhibition as a novel treatment target in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Cognição , Rede Nervosa/fisiopatologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores Purinérgicos P2Y1/metabolismo , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Difosfato de Adenosina/uso terapêutico , Doença de Alzheimer/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/patologia , Humanos , Memória/efeitos dos fármacos , Camundongos Transgênicos , Rede Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Placa Amiloide/metabolismo , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
17.
EMBO Mol Med ; 10(1): 32-47, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29208638

RESUMO

Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aß pores without changing the membrane embedded Aß-oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD-related pathology that should be investigated further.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Benzodioxóis/uso terapêutico , Hipocampo/efeitos dos fármacos , Pirazóis/uso terapêutico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Benzodioxóis/farmacologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Fenótipo , Pirazóis/farmacologia , Memória Espacial/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
18.
Immunity ; 46(6): 1030-1044.e8, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28636953

RESUMO

Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer-deficient microglia expressed more pro-inflammatory cytokines than wild-type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio-resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time.


Assuntos
Hipocampo/metabolismo , MicroRNAs/genética , Microglia/fisiologia , Neurônios/fisiologia , Ribonuclease III/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Reparo do DNA , Feminino , Hipocampo/embriologia , Hipocampo/crescimento & desenvolvimento , Humanos , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/metabolismo , Atividade Motora , Plasticidade Neuronal , Ribonuclease III/genética
19.
Expert Rev Proteomics ; 14(6): 545-559, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28539064

RESUMO

INTRODUCTION: Neurological disorders encompass various pathologies which disrupt normal brain physiology and function. Poor understanding of their underlying molecular mechanisms and their societal burden argues for the necessity of novel prevention strategies, early diagnostic techniques and alternative treatment options to reduce the scale of their expected increase. Areas covered: This review scrutinizes mass spectrometry based approaches used to investigate brain dynamics in various conditions, including neurodegenerative and neuropsychiatric disorders. Different proteomics workflows for isolation/enrichment of specific cell populations or brain regions, sample processing; mass spectrometry technologies, for differential proteome quantitation, analysis of post-translational modifications and imaging approaches in the brain are critically deliberated. Future directions, including analysis of cellular sub-compartments, targeted MS platforms (selected/parallel reaction monitoring) and use of mass cytometry are also discussed. Expert commentary: Here, we summarize and evaluate current mass spectrometry based approaches for determining brain dynamics in health and diseases states, with a focus on neurological disorders. Furthermore, we provide insight on current trends and new MS technologies with potential to improve this analysis.


Assuntos
Encéfalo/metabolismo , Degeneração Neural/genética , Proteoma/genética , Proteômica , Animais , Encéfalo/patologia , Humanos , Degeneração Neural/patologia , Processamento de Proteína Pós-Traducional/genética , Biologia de Sistemas/métodos , Espectrometria de Massas em Tandem
20.
Neuron ; 92(1): 114-125, 2016 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-27641495

RESUMO

Alzheimer's disease (AD) is characterized by cognitive decline and neuronal network dysfunction, but the underlying mechanisms remain unknown. In the hippocampus, microcircuit activity during learning and memory processes is tightly controlled by O-LM interneurons. Here, we investigated the effect of beta-amyloidosis on O-LM interneuron structural and functional connectivity, combining two-photon in vivo imaging of synaptic morphology, awake Ca2+ imaging, and retrograde mono-transsynaptic rabies tracing. We find severely impaired synaptic rewiring that occurs on the O-LM interneuron input and output level in a mouse model of AD. Synaptic rewiring that occurs upon fear learning on O-LM interneuron input level is affected in mice with AD-like pathology. This process requires the release of acetylcholine from septo-hippocampal projections. We identify decreased cholinergic action on O-LM interneurons in APP/PS1 mice as a key pathomechanism that contributes to memory impairment in a mouse model, with potential relevance for human AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Interneurônios/fisiologia , Transtornos da Memória/fisiopatologia , Plasticidade Neuronal/fisiologia , Somatostatina/metabolismo , Acetilcolina/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/efeitos adversos , Precursor de Proteína beta-Amiloide/genética , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Condicionamento Psicológico , Modelos Animais de Doenças , Medo , Glutamato Descarboxilase/genética , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Interneurônios/metabolismo , Interneurônios/patologia , Camundongos , Camundongos Transgênicos , Técnicas de Rastreamento Neuroanatômico , Somatostatina/genética , Sinapses/patologia , Sinapses/fisiologia
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