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1.
Methods Mol Biol ; 2576: 437-451, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36152208

RESUMO

Single-molecule localization microscopy (SMLM) opened new possibilities to study the spatial arrangement of molecular distribution and disease-associated redistribution at a previously unprecedented resolution that was not achievable with optical microscopy approaches. Recent discoveries based on SMLM techniques uncovered specific nanoscale organizational principles of signaling proteins in several biological systems including the chemical synapses in the brain. Emerging data suggest that the spatial arrangement of the molecular players of the endocannabinoid system is also precisely regulated at the nanoscale level in synapses and in other neuronal and glial subcellular compartments. The precise nanoscale distribution pattern is likely to be important to subserve several specific signaling functions of this important messenger system in a cell-type- and subcellular domain-specific manner.STochastic Optical Reconstruction Microscopy (STORM) is an especially suitable SMLM modality for cell-type-specific nanoscale molecular imaging due to its compatibility with traditional diffraction-limited microscopy approaches and classical staining methods. Here, we describe a detailed protocol for STORM imaging in mouse brain tissue samples with a focus on the CB1 cannabinoid receptor, one of the most abundant synaptic receptors in the brain. We also summarize important conceptual and methodical details that are essential for the valid interpretation of single-molecule localization microscopy data.


Assuntos
Endocanabinoides , Microscopia , Animais , Endocanabinoides/metabolismo , Camundongos , Microscopia/métodos , Receptores de Canabinoides , Receptores de Neurotransmissores , Sinapses/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-36029930

RESUMO

Deterioration of inhibitory synapse may be an essential neurological basis underlying abnormal social behaviours. Manipulations that regulate GABAergic transmission are associated with improved behavioural phenotypes in sociability. The synaptic protein, Ephrin-B2 (EB2), plays an important role in the maintenance and reconfiguration of inhibitory synapses in the medial prefrontal cortex (mPFC). However, the inhibitory cell-type specific role of EB2 in the pathophysiology and treatment of social deficits remains unknown. As expected, we revealed that tdTomato-expressing cells were only found in GABAergic neurons instead of excitatory neurons in transgenic EB2-vGATCre mice. This result indicated that depletion of EB2 would occur in those neurons, which further contribute to social deficits. In addition, specific over-expression of mPFC EB2 restored the defective social behaviour abnormalities. These results suggest that the effect of EB2 on social deficits is anatomically and cell-type specific. More importantly, the global upregulation of HDAC4 expression was found in EB2-vGATCre mice. Significant subcellular nuclear shuttling of HDAC4 in vGAT+ neurons was examined and quantified, suggesting a role of nuclear HDAC4 in mediating the mechanism underlying EB2 impairment in vGAT+ neurons. Treatment with LMK235 led to a remarkable rescue of social deficits, thus our data revealed a new domain for the potential utility of HDAC targeting agents to treat social deficits. In conclusion, these results not only revealed a novel molecular mechanism underlying the pathophysiology of social deficits, but also suggested a potential intervention avenue for the treatment of social deficits.


Assuntos
Efrina-B2 , Histona Desacetilases , Animais , Camundongos , Proteínas de Transporte , Efrina-B2/metabolismo , Neurônios GABAérgicos/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Camundongos Transgênicos , Mutação , Sinapses/metabolismo
3.
Behav Brain Res ; 437: 114104, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36100011

RESUMO

Post-stroke depression (PSD) is a common neuropsychiatric complication of stroke, which seriously affects the quality of life and prognosis of patients. Nevertheless, the pathogenesis of PSD remains unclear. In our study, a PSD rat model was established by chronic restraint stress (CRS) combined with middle cerebral artery occlusion (MCAO). Depressive and anxiety-like behaviors were tested, as well as Neuronal loss and Apoptosis. The expression of synapse and p38 MAPK signaling pathway -relevant proteins was detected. Our data indicated that CRS combined with MCAO could induce depression-like and anxiety-like behaviors, which led to neuronal damage, apoptosis, and cellular loss in the left parietal cortex and left hippocampus. Furthermore, CRS combined with MCAO decreased synaptic plasticity in the parietal cortex and left hippocampus. We found that CRS combined with MCAO had activated the p38 MAPK signaling pathway, and decreased the expression of pathway-related proteins MKK6 and MKK3. These results suggested that CRS combined with MCAO could lead to depression-like behavior via neuronal damage, apoptosis and reduced synaptic plasticity, which might be related to the activation of the p38 MAPK pathway. Therefore, it provides novel ideas for the research on the intervention and prevention mechanisms of PSD.


Assuntos
Arteriopatias Oclusivas , Depressão , Infarto da Artéria Cerebral Média , Estresse Psicológico , Acidente Vascular Cerebral , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Ratos , Depressão/etiologia , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/psicologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Qualidade de Vida , Ratos Sprague-Dawley , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/psicologia , Arteriopatias Oclusivas/etiologia , Arteriopatias Oclusivas/metabolismo , Sinapses/metabolismo , Transdução de Sinais , Restrição Física/efeitos adversos , Restrição Física/fisiologia , Restrição Física/psicologia , Doença Crônica , Estresse Psicológico/etiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Apoptose , Ansiedade/etiologia , Ansiedade/metabolismo , Ansiedade/psicologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Neurônios/metabolismo , Neurônios/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo
4.
J Exp Med ; 220(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36378226

RESUMO

CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS). We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. We show that human CD8+ T cells upregulate the expression of ACE2, the Spike receptor, during differentiation to CTLs. CTL preincubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing and cytokine production. These defects were reversed by anti-Spike antibodies interfering with ACE2 binding and reproduced by ACE2 engagement by angiotensin II or anti-ACE2 antibodies, but not by the ACE2 product Ang (1-7). IS defects were also observed ex vivo in CTLs from COVID-19 patients. These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent elimination of infected cells.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Humanos , Enzima de Conversão de Angiotensina 2 , SARS-CoV-2 , Peptidil Dipeptidase A/metabolismo , Sinapses/metabolismo , Ligação Proteica
5.
Synapse ; 77(1): e22253, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36121749

RESUMO

Anorexia nervosa (AN) is a mental illness with the highest rates of mortality and relapse, and no approved pharmacological treatment. Using an animal model of AN, called activity-based anorexia (ABA), we showed earlier that a single intraperitoneal injection of ketamine at a dose of 30 mg/kg (30mgKET), but not 3 mg/kg (3mgKET), has a long-lasting effect upon adolescent females of ameliorating anorexia-like symptoms through the following changes: enhanced food consumption and body weight; reduced running and anxiety-like behavior. However, there were also individual differences in the drug's efficacy. We hypothesized that individual differences in ketamine's ameliorative effects involve drebrin A, an F-actin-binding protein known to be required for the activity-dependent trafficking of NMDA receptors (NMDARs). We tested this hypothesis by electron microscopic quantifications of drebrin A immunoreactivity at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (GABA-IN) in deep layer 1 of prefrontal cortex (PFC) of these mice. Results reveal that (1) the areal density of excitatory synapses on GABA-IN is greater for the 30mgKET group than the 3mgKET group; (2) the proportion of drebrin A+ excitatory synapses is greater for both PN and GABA-IN of 30mgKET than 3mgKET group. Correlation analyses with behavioral measurements revealed that (3) 30mgKET's protection is associated with reduced levels of drebrin A in the cytoplasm of GABA-IN and higher levels at extrasynaptic membranous sites of PN and GABA-IN; (5) altogether pointing to 30mgKET-induced homeostatic plasticity that engages drebrin A at excitatory synapses of both PN and GABA-IN.


Assuntos
Anorexia Nervosa , Ketamina , Camundongos , Feminino , Animais , Ketamina/farmacologia , Anorexia Nervosa/tratamento farmacológico , Anorexia Nervosa/metabolismo , Anorexia/tratamento farmacológico , Anorexia/metabolismo , Individualidade , Sinapses/metabolismo , Modelos Animais de Doenças , Córtex Pré-Frontal/metabolismo , Citoplasma/metabolismo , Ácido gama-Aminobutírico/metabolismo
6.
Neuropsychopharmacology ; 48(1): 21-36, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35577914

RESUMO

Over the last 15 years, the field of neuroscience has evolved toward recognizing the critical role of astroglia in shaping neuronal synaptic activity and along with the pre- and postsynapse is now considered an equal partner in tripartite synaptic transmission and plasticity. The relative youth of this recognition and a corresponding deficit in reagents and technologies for quantifying and manipulating astroglia relative to neurons continues to hamper advances in understanding tripartite synaptic physiology. Nonetheless, substantial advances have been made and are reviewed herein. We review the role of astroglia in synaptic function and regulation of behavior with an eye on how tripartite synapses figure into brain pathologies underlying behavioral impairments in psychiatric disorders, both from the perspective of measures in postmortem human brains and more subtle influences on tripartite synaptic regulation of behavior in animal models of psychiatric symptoms. Our goal is to provide the reader a well-referenced state-of-the-art understanding of current knowledge and predict what we may discover with deeper investigation of tripartite synapses using reagents and technologies not yet available.


Assuntos
Astrócitos , Transtornos Mentais , Animais , Humanos , Adolescente , Astrócitos/fisiologia , Transmissão Sináptica/fisiologia , Sinapses/fisiologia , Neurônios/fisiologia , Plasticidade Neuronal/fisiologia
7.
Neuropsychopharmacology ; 48(1): 37-53, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36100658

RESUMO

Endocannabinoids (eCBs) are lipid neuromodulators that suppress neurotransmitter release, reduce postsynaptic excitability, activate astrocyte signaling, and control cellular respiration. Here, we describe canonical and emerging eCB signaling modes and aim to link adaptations in these signaling systems to pathological states. Adaptations in eCB signaling systems have been identified in a variety of biobehavioral and physiological process relevant to neuropsychiatric disease states including stress-related disorders, epilepsy, developmental disorders, obesity, and substance use disorders. These insights have enhanced our understanding of the pathophysiology of neurological and psychiatric disorders and are contributing to the ongoing development of eCB-targeting therapeutics. We suggest future studies aimed at illuminating how adaptations in canonical as well as emerging cellular and synaptic modes of eCB signaling contribute to disease pathophysiology or resilience could further advance these novel treatment approaches.


Assuntos
Endocanabinoides , Sinapses , Humanos , Endocanabinoides/fisiologia , Transmissão Sináptica , Transdução de Sinais
8.
Neuropsychopharmacology ; 48(1): 54-60, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35995973

RESUMO

Neuronal and synaptic plasticity are widely used terms in the field of psychiatry. However, cellular neurophysiologists have identified two broad classes of plasticity. Hebbian forms of plasticity alter synaptic strength in a synapse specific manner in the same direction of the initial conditioning stimulation. In contrast, homeostatic plasticities act globally over longer time frames in a negative feedback manner to counter network level changes in activity or synaptic strength. Recent evidence suggests that homeostatic plasticity mechanisms can be rapidly engaged, particularly by fast-acting antidepressants such as ketamine to trigger behavioral effects. There is increasing evidence that several neuropsychoactive compounds either directly elicit changes in synaptic activity or indirectly tap into downstream signaling pathways to trigger homeostatic plasticity and subsequent behavioral effects. In this review, we discuss this recent work in the context of a wider paradigm where homeostatic synaptic plasticity mechanisms may provide novel targets for neuropsychiatric treatment advance.


Assuntos
Ketamina , Sinapses , Plasticidade Neuronal/fisiologia , Homeostase/fisiologia , Neurônios , Ketamina/farmacologia
9.
Neuropsychopharmacology ; 48(1): 121-144, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36038780

RESUMO

Synaptic plasticity configures interactions between neurons and is therefore likely to be a primary driver of behavioral learning and development. How this microscopic-macroscopic interaction occurs is poorly understood, as researchers frequently examine models within particular ranges of abstraction and scale. Computational neuroscience and machine learning models offer theoretically powerful analyses of plasticity in neural networks, but results are often siloed and only coarsely linked to biology. In this review, we examine connections between these areas, asking how network computations change as a function of diverse features of plasticity and vice versa. We review how plasticity can be controlled at synapses by calcium dynamics and neuromodulatory signals, the manifestation of these changes in networks, and their impacts in specialized circuits. We conclude that metaplasticity-defined broadly as the adaptive control of plasticity-forges connections across scales by governing what groups of synapses can and can't learn about, when, and to what ends. The metaplasticity we discuss acts by co-opting Hebbian mechanisms, shifting network properties, and routing activity within and across brain systems. Asking how these operations can go awry should also be useful for understanding pathology, which we address in the context of autism, schizophrenia and Parkinson's disease.


Assuntos
Plasticidade Neuronal , Sinapses , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Neurônios , Redes Neurais de Computação , Cálcio , Modelos Neurológicos
10.
Neuropsychopharmacology ; 48(1): 90-103, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36057649

RESUMO

What changes in brain function cause the debilitating symptoms of depression? Can we use the answers to this question to invent more effective, faster acting antidepressant drug therapies? This review provides an overview and update of the converging human and preclinical evidence supporting the hypothesis that changes in the function of excitatory synapses impair the function of the circuits they are embedded in to give rise to the pathological changes in mood, hedonic state, and thought processes that characterize depression. The review also highlights complementary human and preclinical findings that classical and novel antidepressant drugs relieve the symptoms of depression by restoring the functions of these same synapses and circuits. These findings offer a useful path forward for designing better antidepressant compounds.


Assuntos
Depressão , Sinapses , Humanos , Depressão/tratamento farmacológico , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Recompensa , Plasticidade Neuronal
11.
Neuropsychopharmacology ; 48(1): 113-120, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35810199

RESUMO

Activity-dependent synaptic plasticity is a ubiquitous property of the nervous system that allows neurons to communicate and change their connections as a function of past experiences. Through reweighting of synaptic strengths, the nervous system can remodel itself, giving rise to durable memories that create the biological basis for mental function. In healthy individuals, synaptic plasticity undergoes characteristic developmental and aging trajectories. Dysfunctional plasticity, in turn, underlies a wide spectrum of neuropsychiatric disorders including depression, schizophrenia, addiction, and posttraumatic stress disorder. From a mechanistic standpoint, synaptic plasticity spans the gamut of spatial and temporal scales, from microseconds to the lifespan, from microns to the entire nervous system. With the numbers and strengths of synapses changing on such wide scales, there is an important need to develop measurement techniques with complimentary sensitivities and a growing number of approaches are now being harnessed for this purpose. Through hemodynamic measures, structural and tracer imaging, and noninvasive neuromodulation, it is possible to image structural and functional changes that underlie synaptic plasticity and associated behavioral learning. Here we review the mechanisms of neural plasticity and the historical and future trends in techniques that allow imaging of synaptic changes that accompany psychiatric disorders, highlighting emerging therapeutics and the challenges and opportunities accompanying this burgeoning area of study.


Assuntos
Saúde Mental , Plasticidade Neuronal , Humanos , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Neurônios/fisiologia , Aprendizagem/fisiologia
12.
J Theor Biol ; 556: 111326, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36279957

RESUMO

The synaptic tagging and capture (STC) hypothesis not only explain the integration and association of synaptic activities, but also the formation of learning and memory. The synaptic pathways involved in the synaptic tagging and capture phenomenon are called STC pathways. The STC hypothesis provides a potential explanation of the neuronal and synaptic processes underlying the synaptic consolidation of memories. Several mechanisms and molecules have been proposed to explain the process of memory allocation and synaptic tags, respectively. However, a clear link between the STC hypothesis and memory allocation is still missing because the encoding of memories in neural circuits is mainly associated with strongly recurrently connected groups of neurons. To explore the mechanisms of potential synaptic tagging candidates and their involvement in the process of memory allocation, we develop a mathematical model for a single dendritic spine based on five essential criteria of a synaptic tag. By developing a mathematical model, we attempt to understand the roles of the potentially critical molecular networks underlying the STC and the essential attributes of a synaptic tag. We include essential memory molecules in the STC model that have been identified in earlier studies as crucial for STC pathways. CaMKII activation is critical for the setting of the initial tag; however, coordinated activities with other kinases and the biochemical pathways are necessary for the tag to be stable. PKA modulates NMDAR-mediated Ca2+ signalling. Similarly, PKA and ERK crosstalk is essential for Ca2+ - mediated protein synthesis during l-LTP. Our theoretical model explains the quantitative contribution of Tags and protein synthesis during l-LTP in synaptic strength.


Assuntos
Plasticidade Neuronal , Sinapses , Sinapses/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Modelos Teóricos , Potenciação de Longa Duração/fisiologia
13.
Synapse ; 77(1): e22255, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36121930

RESUMO

The regulation of dendritic spine morphology is a critical aspect of neuronal network refinement during development and modulation of neurotransmission. Previous studies revealed that glutamatergic transmission plays a central role in synapse development. AMPA receptors and NMDA receptors regulate spine morphology in an activity dependent manner. However, whether and how Kainate receptors (KARs) regulate synapse development remains poorly understood. In this study, we found that GluK1 and GluK2 may play distinct roles in synapse development. In primary cultured hippocampal neurons, we found overexpression of the calcium-permeable GluK2(Q) receptor variant increased spine length and spine head area compared to overexpression of the calcium-impermeable GluK2(R) variant or EGFP transfected, control neurons, indicating that Q/R editing may play a role in GluK2 regulation of synapse development. Intriguingly, neurons transfected with GluK1(Q) showed decreased spine length and spine head area, while the density of dendritic spines was increased, suggesting that GluK1(Q) and GluK2(Q) have different effects on synaptic development. Swapping the critical domains between GluK2 and GluK1 demonstrated the N-terminal domain (NTD) is responsible for the different effects of GluK1 and GluK2. In conclusion, Kainate receptors GluK1 and GluK2 have distinct roles in regulating spine morphology and development, a process likely relying on the NTD.


Assuntos
Cálcio , Receptores de Ácido Caínico , Receptores de Ácido Caínico/genética , Receptores de AMPA , Sinapses , Receptores de N-Metil-D-Aspartato
14.
Biochem Biophys Res Commun ; 637: 100-107, 2022 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36395691

RESUMO

Recently, we reported that auditory fear conditioning leads to the presynaptic potentiation at lateral amygdala to basal amygdala (LA-BA) synapses that shares the mechanism with high-frequency stimulation (HFS)-induced long-term potentiation (LTP) ex vivo. In the present study, we further examined the molecular mechanisms underlying the HFS-induced presynaptic LTP. We found that a presynaptic elevation of Ca2+ was required for the LTP induction. Interestingly, the blockade of presynaptic but not postsynaptic HCN channels with ZD7288 completely abolished LTP induction. While ZD7288 did not alter basal synaptic transmission, the blocker fully reversed previously established LTP, indicating that HCN channels are also required for the maintenance of LTP. Indeed, HCN3 and HCN4 channels were preferentially localized in the presynaptic boutons of LA afferents. Furthermore, an inhibition of either GABAB receptors or GIRK channels eliminated the inhibitory effect of HCN blockade on the LTP induction. Collectively, we suggest that activation of presynaptic HCN channels may counteract membrane hyperpolarization during tetanic stimulation, and thereby contributes to the presynaptic LTP at LA-BA synapses.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Potenciação de Longa Duração , Sinapses , Transmissão Sináptica , Terminações Pré-Sinápticas
15.
Mol Cell Neurosci ; 123: 103793, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36396040

RESUMO

Research in the past twenty years or so has revealed that neurons synthesize and degrade proteins at their synapses to enable synaptic proteome remodelling on demand and in real-time. Here we provide a quantitative overview of the decentralized neuronal protein-turnover logistics. We first analyse the huge neuronal protein turnover demand that arises from subcellular compartments outside the cell body, followed by an overview of key quantities and modulation strategies in neuronal protein turnover logistics. In the end, we briefly review recent progress in neuronal local protein synthesis and summarize diverse protein-degradation mechanisms that are found near synapses.


Assuntos
Neurônios , Sinapses , Proteólise , Proteoma
16.
Nature ; 612(7938): 43-50, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36450907

RESUMO

Artificial intelligence now advances by performing twice as many floating-point multiplications every two months, but the semiconductor industry tiles twice as many multipliers on a chip every two years. Moreover, the returns from tiling these multipliers ever more densely now diminish because signals must travel relatively farther and farther. Although travel can be shortened by stacking tiled multipliers in a three-dimensional chip, such a solution acutely reduces the available surface area for dissipating heat. Here I propose to transcend this three-dimensional thermal constraint by moving away from learning with synapses to learning with dendrites. Synaptic inputs are not weighted precisely but rather ordered meticulously along a short stretch of dendrite, termed dendrocentric learning. With the help of a computational model of a dendrite and a conceptual model of a ferroelectric device that emulates it, I illustrate how dendrocentric learning artificial intelligence-or synthetic intelligence for short-could run not with megawatts in the cloud but rather with watts on a smartphone.


Assuntos
Inteligência Artificial , Aprendizagem , Inteligência , Sinapses , Temperatura Alta
17.
Prog Mol Biol Transl Sci ; 193(1): 119-144, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36357074

RESUMO

The past decades have witnessed a dogmatic shift from glia as supporting cells in the nervous system to their active roles in neurocentric functions. Neurons and glia communicate and show bidirectional responses through tripartite synapses. Studies across species indicate that neurotransmitters released by neurons are perceived by glial receptors, which allow for gliotransmitter release. These gliotransmitters can result in activation of neurons via neuronal GPCR receptors. However, studies of these molecular interactions are in their infancy. Caenorhabditis elegans has a conserved neuron-glia architectural repertoire with molecular and functional resemblance to mammals. Further, glia in C. elegans can be manipulated through ablation and mutations allowing for deciphering of glial dependent processes in vivo at single glial resolutions. Here, we will review recent findings from vertebrate and invertebrate organisms with a focus on how C. elegans can be used to advance our understanding of neuron-glia interactions through GPCRs.


Assuntos
Caenorhabditis elegans , Neuroglia , Humanos , Animais , Caenorhabditis elegans/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Receptores Acoplados a Proteínas G , Mamíferos
18.
Nat Commun ; 13(1): 6836, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369219

RESUMO

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders.


Assuntos
Transtornos do Neurodesenvolvimento , Sinapses , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Fator de Transcrição PAX6/genética , Fator de Transcrição PAX6/metabolismo , Fenótipo , Sinapses/metabolismo
19.
Nat Commun ; 13(1): 6898, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371405

RESUMO

Stress can cause overconsumption of palatable high caloric food. Despite the important role of stress eating in obesity and (binge) eating disorders, its underlying neural mechanisms remain unclear. Here we demonstrate in mice that stress alters lateral hypothalamic area (LHA) control over the ventral tegmental area (VTA), thereby promoting overconsumption of palatable food. Specifically, we show that glutamatergic LHA neurons projecting to the VTA are activated by social stress, after which their synapses onto dopamine neurons are potentiated via AMPA receptor subunit alterations. We find that stress-driven strengthening of these specific synapses increases LHA control over dopamine output in key target areas like the prefrontal cortex. Finally, we demonstrate that while inducing LHA-VTA glutamatergic potentiation increases palatable fat intake, reducing stress-driven potentiation of this connection prevents such stress eating. Overall, this study provides insights in the neural circuit adaptations caused by stress that drive overconsumption of palatable food.


Assuntos
Região Hipotalâmica Lateral , Área Tegmentar Ventral , Camundongos , Animais , Neurônios Dopaminérgicos , Sinapses , Receptores de AMPA
20.
Sci Rep ; 12(1): 18521, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323869

RESUMO

Specialized sound localization circuit development requires synapse strengthening, refinement, and pruning. Many of these functions are carried out by microglia, immune cells that aid in regulating neurogenesis, synaptogenesis, apoptosis, and synaptic removal. We previously showed that postnatal treatment with BLZ945 (BLZ), an inhibitor of colony stimulating factor 1 receptor (CSF1R), eliminates microglia in the brainstem and disables calyceal pruning and maturation of astrocytes in the medial nucleus of the trapezoid body (MNTB). BLZ treatment results in elevated hearing thresholds and delayed signal propagation as measured by auditory brainstem responses (ABR). However, when microglia repopulate the brain following the cessation of BLZ, most of the deficits are repaired. It is unknown whether this recovery is achievable without the return of microglia. Here, we induced sustained microglial elimination with a two-drug approach using BLZ and PLX5622 (PLX). We found that BLZ/PLX treated mice had impaired calyceal pruning, diminished astrocytic GFAP in the lateral, low frequency, region of MNTB, and elevated glycine transporter 2 (GLYT2) levels. BLZ/PLX treated mice had elevated hearing thresholds, diminished peak amplitudes, and altered latencies and inter-peak latencies. These findings suggest that microglia are required to repopulate the brain in order to rectify deficits from their ablation.


Assuntos
Microglia , Corpo Trapezoide , Animais , Camundongos , Microglia/fisiologia , Tronco Encefálico , Audição , Sinapses
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