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1.
Cell ; 173(1): 140-152.e15, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29570993

RESUMO

Hunger and pain are two competing signals that individuals must resolve to ensure survival. However, the neural processes that prioritize conflicting survival needs are poorly understood. We discovered that hunger attenuates behavioral responses and affective properties of inflammatory pain without altering acute nociceptive responses. This effect is centrally controlled, as activity in hunger-sensitive agouti-related protein (AgRP)-expressing neurons abrogates inflammatory pain. Systematic analysis of AgRP projection subpopulations revealed that the neural processing of hunger and inflammatory pain converge in the hindbrain parabrachial nucleus (PBN). Strikingly, activity in AgRP → PBN neurons blocked the behavioral response to inflammatory pain as effectively as hunger or analgesics. The anti-nociceptive effect of hunger is mediated by neuropeptide Y (NPY) signaling in the PBN. By investigating the intersection between hunger and pain, we have identified a neural circuit that mediates competing survival needs and uncovered NPY Y1 receptor signaling in the PBN as a target for pain suppression.


Assuntos
Neurônios/metabolismo , Dor/patologia , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Analgésicos Opioides/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Dieta , Comportamento Alimentar/efeitos dos fármacos , Formaldeído/toxicidade , Glutamato Descarboxilase/metabolismo , Locomoção/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Neurônios/efeitos dos fármacos , Dor/etiologia , Dor/metabolismo , Núcleos Parabraquiais/efeitos dos fármacos , Núcleos Parabraquiais/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Transdução de Sinais
2.
Nature ; 599(7885): 471-476, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34732892

RESUMO

Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.


Assuntos
Linfócitos B/metabolismo , Interleucina-10/imunologia , Macrófagos/metabolismo , Neoplasias/imunologia , Ácido gama-Aminobutírico/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Feminino , Deleção de Genes , Glutamato Descarboxilase/deficiência , Glutamato Descarboxilase/genética , Humanos , Inflamação/imunologia , Inflamação/prevenção & controle , Macrófagos/imunologia , Masculino , Camundongos , Neoplasias/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Ácido gama-Aminobutírico/biossíntese
3.
Proc Natl Acad Sci U S A ; 121(24): e2311570121, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38830095

RESUMO

Even a transient period of hearing loss during the developmental critical period can induce long-lasting deficits in temporal and spectral perception. These perceptual deficits correlate with speech perception in humans. In gerbils, these hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. Therefore, we developed viral vectors to express proteins that would upregulate gerbil postsynaptic inhibitory receptor subunits (GABAA, Gabra1; GABAB, Gabbr1b) in pyramidal neurons, and an enzyme that mediates GABA synthesis (GAD65) presynaptically in parvalbumin-expressing interneurons. A transient period of developmental hearing loss during the auditory critical period significantly impaired perceptual performance on two auditory tasks: amplitude modulation depth detection and spectral modulation depth detection. We then tested the capacity of each vector to restore perceptual performance on these auditory tasks. While both GABA receptor vectors increased the amplitude of cortical inhibitory postsynaptic potentials, only viral expression of postsynaptic GABAB receptors improved perceptual thresholds to control levels. Similarly, presynaptic GAD65 expression improved perceptual performance on spectral modulation detection. These findings suggest that recovering performance on auditory perceptual tasks depends on GABAB receptor-dependent transmission at the auditory cortex parvalbumin to pyramidal synapse and point to potential therapeutic targets for developmental sensory disorders.


Assuntos
Córtex Auditivo , Gerbillinae , Perda Auditiva , Animais , Córtex Auditivo/metabolismo , Córtex Auditivo/fisiopatologia , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Receptores de GABA-B/metabolismo , Receptores de GABA-B/genética , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Receptores de GABA-A/metabolismo , Receptores de GABA-A/genética , Parvalbuminas/metabolismo , Parvalbuminas/genética , Percepção Auditiva/fisiologia , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Vetores Genéticos/genética
4.
Proc Natl Acad Sci U S A ; 121(35): e2406928121, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39178233

RESUMO

Autism spectrum disorders (ASD) can be caused by environmental factors. These factors act early in the development of the nervous system and induce stereotyped repetitive behaviors and diminished social interactions, among other outcomes. Little is known about how these behaviors are produced. In pregnant women, delivery of valproic acid (VPA) (to control seizure activity or stabilize mood) or immune activation by a virus increases the incidence of ASD in offspring. We found that either VPA or Poly Inosine:Cytosine (which mimics a viral infection), administered at mouse embryonic day 12.5, induced a neurotransmitter switch from GABA to glutamate in PV- and CCK-expressing interneurons in the medial prefrontal cortex by postnatal day 10. The switch was present for only a brief period during early postnatal development, observed in male and female mice at postnatal day 21 and reversed in both males and females by postnatal day 30. At postnatal day 90, male mice exhibited stereotyped repetitive behaviors and diminished social interaction while female mice exhibited only stereotyped repetitive behavior. Transfecting GAD1 in PV- and CCK-expressing interneurons at postnatal day 10, to reintroduce GABA expression, overrode the switch and prevented expression of autistic-like behavior. These findings point to an important role of neurotransmitter switching in mediating the environmental causes of autism.


Assuntos
Ácido Valproico , Ácido gama-Aminobutírico , Animais , Feminino , Camundongos , Masculino , Gravidez , Ácido Valproico/toxicidade , Ácido gama-Aminobutírico/metabolismo , Interneurônios/metabolismo , Animais Recém-Nascidos , Comportamento Animal , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Transtorno Autístico/etiologia , Transtorno Autístico/metabolismo , Ácido Glutâmico/metabolismo , Neurotransmissores/metabolismo , Poli I-C , Córtex Pré-Frontal/metabolismo , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/patologia , Colecistocinina/metabolismo , Parvalbuminas/metabolismo , Camundongos Endogâmicos C57BL , Comportamento Estereotipado/efeitos dos fármacos
5.
Nature ; 583(7816): 421-424, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32641825

RESUMO

The suprachiasmatic nucleus (SCN) serves as the body's master circadian clock that adaptively coordinates changes in physiology and behaviour in anticipation of changing requirements throughout the 24-h day-night cycle1-4. For example, the SCN opposes overnight adipsia by driving water intake before sleep5,6, and by driving the secretion of anti-diuretic hormone7,8 and lowering body temperature9,10 to reduce water loss during sleep11. These responses can also be driven by central osmo-sodium sensors to oppose an unscheduled rise in osmolality during the active phase12-16. However, it is unknown whether osmo-sodium sensors require clock-output networks to drive homeostatic responses. Here we show that a systemic salt injection (hypertonic saline) given at Zeitgeber time 19-a time at which SCNVP (vasopressin) neurons are inactive-excited SCNVP neurons and decreased non-shivering thermogenesis (NST) and body temperature. The effects of hypertonic saline on NST and body temperature were prevented by chemogenetic inhibition of SCNVP neurons and mimicked by optogenetic stimulation of SCNVP neurons in vivo. Combined anatomical and electrophysiological experiments revealed that osmo-sodium-sensing organum vasculosum lamina terminalis (OVLT) neurons expressing glutamic acid decarboxylase (OVLTGAD) relay this information to SCNVP neurons via an excitatory effect of γ-aminobutyric acid (GABA). Optogenetic activation of OVLTGAD neuron axon terminals excited SCNVP neurons in vitro and mimicked the effects of hypertonic saline on NST and body temperature in vivo. Furthermore, chemogenetic inhibition of OVLTGAD neurons blunted the effects of systemic hypertonic saline on NST and body temperature. Finally, we show that hypertonic saline significantly phase-advanced the circadian locomotor activity onset of mice. This effect was mimicked by optogenetic activation of the OVLTGAD→ SCNVP pathway and was prevented by chemogenetic inhibition of OVLTGAD neurons. Collectively, our findings provide demonstration that clock time can be regulated by non-photic physiologically relevant cues, and that such cues can drive unscheduled homeostatic responses via clock-output networks.


Assuntos
Relógios Circadianos/fisiologia , Vias Neurais , Neurônios/metabolismo , Sódio/metabolismo , Núcleo Supraquiasmático/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Relógios Circadianos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Ingestão de Líquidos/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Optogenética , Organum Vasculosum/citologia , Organum Vasculosum/efeitos dos fármacos , Organum Vasculosum/enzimologia , Organum Vasculosum/fisiologia , Concentração Osmolar , Solução Salina Hipertônica/administração & dosagem , Solução Salina Hipertônica/metabolismo , Solução Salina Hipertônica/farmacologia , Sódio/administração & dosagem , Sódio/farmacologia , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/efeitos dos fármacos , Vasopressinas/metabolismo
6.
J Neurosci ; 44(25)2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38729762

RESUMO

Inhibitory neurons embedded within mammalian neural circuits shape breathing, walking, and other rhythmic motor behaviors. At the core of the neural circuit controlling breathing is the preBötzinger Complex (preBötC), where GABAergic (GAD1/2+) and glycinergic (GlyT2+) neurons are functionally and anatomically intercalated among glutamatergic Dbx1-derived (Dbx1+) neurons that generate rhythmic inspiratory drive. The roles of these preBötC inhibitory neurons in breathing remain unclear. We first characterized the spatial distribution of molecularly defined preBötC inhibitory subpopulations in male and female neonatal double reporter mice expressing either tdTomato or EGFP in GlyT2+, GAD1+, or GAD2+ neurons. We found that the majority of preBötC inhibitory neurons expressed both GlyT2 and GAD2 while a much smaller subpopulation also expressed GAD1. To determine the functional role of these subpopulations, we used holographic photostimulation, a patterned illumination technique, in rhythmically active medullary slices from neonatal Dbx1tdTomato;GlyT2EGFP and Dbx1tdTomato;GAD1EGFP double reporter mice of either sex. Stimulation of 4 or 8 preBötC GlyT2+ neurons during endogenous rhythm prolonged the interburst interval in a phase-dependent manner and increased the latency to burst initiation when bursts were evoked by stimulation of Dbx1+ neurons. In contrast, stimulation of 4 or 8 preBötC GAD1+ neurons did not affect interburst interval or latency to burst initiation. Instead, photoactivation of GAD1+ neurons during the inspiratory burst prolonged endogenous and evoked burst duration and decreased evoked burst amplitude. We conclude that GlyT2+/GAD2+ neurons modulate breathing rhythm by delaying burst initiation while a smaller GAD1+ subpopulation shapes inspiratory patterning by altering burst duration and amplitude.


Assuntos
Inalação , Animais , Camundongos , Feminino , Masculino , Inalação/fisiologia , Inibição Neural/fisiologia , Bulbo/fisiologia , Bulbo/citologia , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Camundongos Transgênicos , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Centro Respiratório/fisiologia , Centro Respiratório/citologia , Neurônios/fisiologia , Periodicidade , Animais Recém-Nascidos
7.
Dev Biol ; 515: 112-120, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39048051

RESUMO

Hormonal imbalance during pregnancy is a risk factor for neuropsychiatric impairment in the offspring. It has been suggested that hypothyroidism leads to dysfunction of cortical GABAergic interneurons and inhibitory system development that in turn underlies impairment of the central nervous system. Here we investigated how gestational hypothyroidism affected offspring GABAergic system development as well as redox regulation parameters, because of previous links identified between the two. Experimental Gestational Hypothyroidism (EGH) was induced in CD-1 mice with 0.02% methimazole (MMI) in drinking water from embryonic day 9 (E9) until tissue collection at embryonic day 14 (E14) or E18. We examined GABAergic cell distribution and inhibitory system development gene expression as well as redox relevant gene expression and direct measures across all embryos regardless of sex. Intrauterine restriction of maternal thyroid hormones significantly impacted both of these outcomes in brain, as well as altering redox regulation in the placenta. GAD67+ neuronal migration was reduced, accompanied by a disruption in gene expression influencing GABAergic cell migration and cortical inhibitory neural system development. EGH also altered embryonic brain gene expression of Gpx1, Nfe2l2, Cat levels in the dorsal E14 brains. Additionally, EGH resulted in elevated TBARS, Gpx1 and Nfe2l2 in the ventral E18 brains. Furthermore, EGH downregulated placental Gpx1 gene expression at E14 and increased protein oxidation at E18. These findings support the hypothesis that sufficient maternal thyroid hormone supply to the fetus influences central nervous system development, including processes of GABAergic system development and redox equilibrium.


Assuntos
Encéfalo , Neurônios GABAérgicos , Glutationa Peroxidase GPX1 , Glutationa Peroxidase , Hipotireoidismo , Estresse Oxidativo , Animais , Feminino , Gravidez , Hipotireoidismo/metabolismo , Camundongos , Encéfalo/metabolismo , Encéfalo/embriologia , Neurônios GABAérgicos/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/genética , Metimazol , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Movimento Celular , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Masculino , Placenta/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo
8.
EMBO J ; 40(21): e107277, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34558085

RESUMO

The dorsal and ventral human telencephalons contain different neuronal subtypes, including glutamatergic, GABAergic, and cholinergic neurons, and how these neurons are generated during early development is not well understood. Using scRNA-seq and stringent validations, we reveal here a developmental roadmap for human telencephalic neurons. Both dorsal and ventral telencephalic radial glial cells (RGs) differentiate into neurons via dividing intermediate progenitor cells (IPCs_div) and early postmitotic neuroblasts (eNBs). The transcription factor ASCL1 plays a key role in promoting fate transition from RGs to IPCs_div in both regions. RGs from the regionalized neuroectoderm show heterogeneity, with restricted glutamatergic, GABAergic, and cholinergic differentiation potencies. During neurogenesis, IPCs_div gradually exit the cell cycle and branch into sister eNBs to generate distinct neuronal subtypes. Our findings highlight a general RGs-IPCs_div-eNBs developmental scheme for human telencephalic progenitors and support that the major neuronal fates of human telencephalon are predetermined during dorsoventral regionalization with neuronal diversity being further shaped during neurogenesis and neural circuit integration.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem da Célula/genética , Regulação da Expressão Gênica no Desenvolvimento , Neurogênese/genética , Neurônios/metabolismo , Telencéfalo/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Ciclo Celular/genética , Diferenciação Celular , Colina/metabolismo , Proteína Duplacortina/genética , Proteína Duplacortina/metabolismo , Feto , Ontologia Genética , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Anotação de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/classificação , Neurônios/citologia , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Transdução de Sinais , Estatmina/genética , Estatmina/metabolismo , Telencéfalo/citologia , Telencéfalo/crescimento & desenvolvimento , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ácido gama-Aminobutírico/metabolismo
9.
Mol Psychiatry ; 29(10): 3128-3140, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38684795

RESUMO

Schizophrenia (SCZ) is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. The etiology behind the disorder remains elusive although it is hypothesized to be associated with the aberrant response to neurotransmitters, such as dopamine and glutamate. Therefore, investigating the link between dysregulated metabolites and distorted neurodevelopment holds promise to offer valuable insights into the underlying mechanism of this complex disorder. In this study, we aimed to explore a presumed correlation between the transcriptome and the metabolome in a SCZ model based on patient-derived induced pluripotent stem cells (iPSCs). For this, iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at various developmental stages, reflecting neuroepithelial-like cells, radial glia, young and mature neurons. The samples were analyzed by both RNA-sequencing and targeted metabolomics and the two modalities were used to construct integrative networks in silico. This multi-omics analysis revealed significant perturbations in the polyamine and gamma-aminobutyric acid (GABA) biosynthetic pathways during rosette maturation in SCZ lines. We particularly observed the downregulation of the glutamate decarboxylase encoding genes GAD1 and GAD2, as well as their protein product GAD65/67 and their biochemical product GABA in SCZ samples. Inhibition of ornithine decarboxylase resulted in further decrease of GABA levels suggesting a compensatory activation of the ornithine/putrescine pathway as an alternative route for GABA production. These findings indicate an imbalance of cortical excitatory/inhibitory dynamics occurring during early neurodevelopmental stages in SCZ. Our study supports the hypothesis of disruption of inhibitory circuits to be causative for SCZ and establishes a novel in silico approach that enables for integrative correlation of metabolic and transcriptomic data of psychiatric disease models.


Assuntos
Células-Tronco Pluripotentes Induzidas , Metabolômica , Neurônios , Esquizofrenia , Ácido gama-Aminobutírico , Esquizofrenia/metabolismo , Esquizofrenia/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Metabolômica/métodos , Ácido gama-Aminobutírico/metabolismo , Neurônios/metabolismo , Transcriptoma/genética , Genômica/métodos , Diferenciação Celular/fisiologia , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Metaboloma
10.
Pflugers Arch ; 476(11): 1761-1775, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39210062

RESUMO

Taste buds contain 2 types of GABA-producing cells: sour-responsive Type III cells and glial-like Type I cells. The physiological role of GABA, released by Type III cells is not fully understood. Here, we investigated the role of GABA released from Type III cells using transgenic mice lacking the expression of GAD67 in taste bud cells (Gad67-cKO mice). Immunohistochemical experiments confirmed the absence of GAD67 in Type III cells of Gad67-cKO mice. Furthermore, no difference was observed in the expression and localization of cell type markers, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2), gustducin, and carbonic anhydrase 4 (CA4) in taste buds between wild-type (WT) and Gad67-cKO mice. Short-term lick tests demonstrated that both WT and Gad67-cKO mice exhibited normal licking behaviors to each of the five basic tastants. Gustatory nerve recordings from the chorda tympani nerve demonstrated that both WT and Gad67-cKO mice similarly responded to five basic tastants when they were applied individually. However, gustatory nerve responses to sweet-sour mixtures were significantly smaller than the sum of responses to each tastant in WT mice but not in Gad67-cKO mice. In summary, elimination of GABA signalling by sour-responsive Type III taste cells eliminates the inhibitory cell-cell interactions seen with application of sour-sweet mixtures.


Assuntos
Glutamato Descarboxilase , Papilas Gustativas , Paladar , Ácido gama-Aminobutírico , Animais , Papilas Gustativas/metabolismo , Papilas Gustativas/fisiologia , Ácido gama-Aminobutírico/metabolismo , Camundongos , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Paladar/fisiologia , Transdução de Sinais/fisiologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Nervo da Corda do Tímpano/fisiologia
11.
J Neurochem ; 168(9): 2587-2600, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38705582

RESUMO

Fear overgeneralization is widely accepted as a pathogenic marker of post-traumatic stress disorder (PTSD). Recently, GABAergic interneurons have been regarded as key players in the regulation of fear memory. The role of hippocampal GABAergic interneurons in contextual fear generalization of PTSD remains incompletely understood. In the present study, we established a rat model of PTSD with inescapable foot shocks (IFS) and observed the loss of GABAergic interneuron phenotype in the hippocampal cornu ammonis-1 (CA1) subfield. To determine whether the loss of GABAergic interneuron phenotype was associated with fear generalization in PTSD rats, we used adeno-associated virus (AAV) to reduce the expression of GAD67 in CA1 and observed its effect on fear generalization. The results showed that the reduction of GAD67 in CA1 enhanced contextual fear generalization in rats. We investigated whether the PERK pathway was involved in the GABAergic interneuron injury. Increased expression of p-PERK, CHOP, and Caspase12 in GABAergic interneurons of PTSD rats was observed. Then, we used salubrinal, an endoplasmic reticulum stress inhibitor, to modulate the PERK pathway. The salubrinal treatment significantly protected the GABAergic interneurons and relieved fear generalization in PTSD rats. In addition, the results showed that salubrinal down-regulated the expression of CHOP and Caspase12 in GABAergic interneurons of PTSD rats. In conclusion, this study provided evidence that the loss of GABAergic interneuron phenotype in CA1 may contribute to contextual fear generalization in PTSD. The PERK pathway is involved in the GABAergic interneuron injury of PTSD rats and modulating it can protect GABAergic interneurons and constrain contextual fear generalization.


Assuntos
Região CA1 Hipocampal , Medo , Neurônios GABAérgicos , Interneurônios , Ratos Sprague-Dawley , Transtornos de Estresse Pós-Traumáticos , Animais , Ratos , Interneurônios/metabolismo , Medo/fisiologia , Medo/psicologia , Masculino , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia , Região CA1 Hipocampal/metabolismo , Neurônios GABAérgicos/metabolismo , Generalização Psicológica/fisiologia , Glutamato Descarboxilase/metabolismo
12.
Neurobiol Dis ; 200: 106619, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39079581

RESUMO

It is well established that hearing loss can lead to widespread plasticity within the central auditory pathway, which is thought to contribute to the pathophysiology of audiological conditions such as tinnitus and hyperacusis. Emerging evidence suggests that hearing loss can also result in plasticity within brain regions involved in higher-level cognitive functioning like the prefrontal cortex; findings which may underlie the association between hearing loss and cognitive impairment documented in epidemiological studies. Using the 40-Hz auditory steady state response to assess sound-evoked gamma oscillations, we previously showed that noise-induced hearing loss results in impaired gamma phase coherence within the prefrontal but not the auditory cortex. To determine whether region-specific structural or molecular changes accompany this differential plasticity following hearing loss, in the present study we utilized Golgi-Cox staining to assess dendritic organization and synaptic density, as well as Western blotting to measure changes in synaptic signaling proteins in these cortical regions. We show that following noise exposure, impaired gamma phase coherence within the prefrontal cortex is accompanied by alterations in pyramidal cell dendritic morphology and decreased expression of proteins involved in GABAergic (GAD65) and glutamatergic (NR2B) neurotransmission; findings that were not observed in the auditory cortex, where gamma phase coherence remained unchanged post-noise exposure. In contrast to the noise-induced effects we observed in the prefrontal cortex, plasticity in the auditory cortex was characterized by an increase in NR2B suggesting increased excitability, as well as increases in the synaptic proteins PSD95 and synaptophysin within the auditory cortex. Overall, our results highlight the disparate effect of noise-induced hearing loss on auditory and higher-level brain regions as well as potential structural and molecular mechanisms by which hearing loss may contribute to impaired cognitive and sensory functions mediated by the prefrontal and auditory cortices.


Assuntos
Córtex Auditivo , Perda Auditiva Provocada por Ruído , Córtex Pré-Frontal , Perda Auditiva Provocada por Ruído/fisiopatologia , Perda Auditiva Provocada por Ruído/patologia , Perda Auditiva Provocada por Ruído/metabolismo , Córtex Auditivo/metabolismo , Córtex Auditivo/fisiopatologia , Córtex Auditivo/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Animais , Masculino , Plasticidade Neuronal/fisiologia , Glutamato Descarboxilase/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Dendritos/patologia , Dendritos/metabolismo , Ritmo Gama/fisiologia , Células Piramidais/metabolismo , Células Piramidais/patologia , Ratos
13.
J Clin Immunol ; 44(6): 140, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38829425

RESUMO

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic disease caused by mutations in the autoimmune regulator gene. Although the disease-associated autoantibodies mostly target endocrine organs, autoantibodies from patients with APS-1 bind also to rat brain structures. The patients often have GAD65-antibodies, that can cause autoimmune encephalitis. However, neurological manifestations of APS-1 have not been systematically explored. We conducted a retrospective chart review on 44 Finnish patients with APS-1 (median age 38 years, 61% females) and collected all their neurological diagnoses. To assess the prevalence of serum antineuronal antibodies in APS-1, serum samples of 24 patients (median age 36 years, 63% females) were analyzed using a fixed cell-based assay. Of the 44 APS-1 patients, 10 (23%) had also received a diagnosis of a neurological disease. Of these neurological comorbidities, migraine (n = 7; 16%), central nervous system infections (n = 3; 7%), and epilepsy (n = 2; 5%) were the most prevalent. Other diagnoses recorded for single patients were axonal sensorimotor polyneuropathy, essential tremor, idiopathic intracranial hypertension, ischemic stroke, and trigeminal neuralgia. Serum antineuronal antibodies were detected in 42% of patients tested (10/24, 50% females, median age 42 years), GAD65 antibodies being the most common finding. Antibodies against glycine and aquaporin 4 were found in low titers. In four patients, relatively high titers of GAD65 antibodies without coexisting type 1 diabetes were found, but none presented with GAD65-encephalitis. Our study suggests an association between APS-1 and neurological disorders, the mechanisms of which are to be further investigated.


Assuntos
Autoanticorpos , Poliendocrinopatias Autoimunes , Humanos , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/epidemiologia , Poliendocrinopatias Autoimunes/sangue , Feminino , Masculino , Adulto , Autoanticorpos/sangue , Autoanticorpos/imunologia , Pessoa de Meia-Idade , Finlândia/epidemiologia , Prevalência , Estudos Retrospectivos , Estudos de Coortes , Adulto Jovem , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/etiologia , Neurônios/imunologia , Adolescente , Glutamato Descarboxilase/imunologia , Idoso
14.
Immunogenetics ; 76(5-6): 335-349, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39276210

RESUMO

This study aimed to investigate the prevalence of insulin autoantibody (IAA), glutamic acid decarboxylase antibody (GADA), and insulinoma-associated antigen-2 antibody (IA-2A) in type 1 diabetes (T1D) children based on the presence of predisposing HLA-II alleles. Additionally, to assess the sequence homology between autoantigens of islet cells and selected proteins derived from gut bacteria in terms of their binding capacities to HLA risk alleles, HLA-DRB1/DQB1 alleles were determined by PCR-SSOP in 111 T1D children (probands) along with 222 parents and 133 siblings. Autoantibodies were measured by ELISA, and in silico analysis was run as follows: protein extraction, homology and epitope prediction, peptide alignment, and HLA-peptide docking. Higher significant frequencies of DRB1*03:01, DQB1*02:01, and DQB1*03:02 alleles and DRB1*03:01 ~ DQB1*02:01 haplotype and lower frequencies of DRB1*11:01, DRB1*14:01, and DQB1*03:01 alleles were found in probands compared to parents and siblings. DRB1*11:01 ~ DQB1*03:01, DRB1*14:01 ~ DQB1*05:03, and DRB1*15:01-DQB1*06:02 haplotypes were significantly less frequent in the probands compared to parents. Out of 111 probands, 21 were seronegative, 90 tested positive for one autoantibody, and 15 showed the concurrent presence of three autoantibodies. Logistic regression analysis revealed that DRB1*04 ~ DQB1*03:02 haplotype was associated with the induction of GADA and IA-2A, while DRB1*11:01 ~ DQB1*03:01 was associated with seronegativity. Epitopes derived from GAD and gut bacteria showed strong binding capacities to HLA risk alleles. Due to the sequence similarities between gut bacteria-derived proteins and islet cell autoantigens and their potential for binding to HLA risk alleles, dysbiosis of gut microbiota can be considered another risk factor for the development of T1D, especially in genetically susceptible individuals.


Assuntos
Alelos , Autoanticorpos , Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Predisposição Genética para Doença , Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Humanos , Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/microbiologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Cadeias beta de HLA-DQ/genética , Cadeias beta de HLA-DQ/imunologia , Criança , Masculino , Feminino , Microbioma Gastrointestinal/imunologia , Pré-Escolar , Adolescente , Haplótipos , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/genética , Simulação por Computador , Glutamato Descarboxilase/imunologia , Glutamato Descarboxilase/genética
15.
J Autoimmun ; 146: 103228, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38642507

RESUMO

CD6 is a glycoprotein expressed on CD4 and CD8 T cells involved in immunoregulation. CD318 has been identified as a CD6 ligand. The role of CD318 in T cell immunity is restricted as it has only been investigated in a few mice autoimmune models but not in human diseases. CD318 expression was thought to be limited to mesenchymal-epithelial cells and, therefore, contribute to CD6-mediated T cell activation in the CD318-expressing tissue rather than through interaction with antigen-presenting cells. Here, we report CD318 expression in a subpopulation of CD318+ myeloid dendritic (mDC), whereas the other peripheral blood populations were CD318 negative. However, CD318 can be induced by activation: a subset of monocytes treated with LPS and IFNγ and in vitro monocyte derived DCs were CD318+. We also showed that recombinant CD318 inhibited T cell function. Strikingly, CD318+ DCs suppressed the proliferation of autoreactive T cells specific for GAD65, a well-known targeted self-antigen in Type 1 Diabetes (T1D). Our study provides new insight into the role of the CD318/CD6 axis in the immunopathogenesis of inflammation, suggesting a novel immunoregulatory role of CD318 in T cell-mediated autoimmune diseases and identifying a potential novel immune checkpoint inhibitor as a target for intervention in T1D which is an unmet therapeutic need.


Assuntos
Antígenos CD , Autoantígenos , Moléculas de Adesão Celular , Células Dendríticas , Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Ativação Linfocitária , Humanos , Antígenos CD/metabolismo , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígenos de Diferenciação de Linfócitos T/imunologia , Autoantígenos/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Glutamato Descarboxilase , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo
16.
New Phytol ; 243(3): 1137-1153, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38877712

RESUMO

Bacterial pathogens inject effector proteins inside plant cells to manipulate cellular functions and achieve a successful infection. The soil-borne pathogen Ralstonia solanacearum (Smith), the causal agent of bacterial wilt disease, secretes > 70 different effectors inside plant cells, although only a handful of them have been thoroughly characterized. One of these effectors, named RipI, is required for full R. solanacearum pathogenicity. RipI associates with plant glutamate decarboxylases (GADs) to promote the accumulation of gamma-aminobutyric acid (GABA), which serves as bacterial nutrient. In this work, we found that RipI can also suppress plant immune responses to bacterial elicitors, which seems to be unrelated to the ability of RipI to induce GABA accumulation and plant cell death. A detailed characterization of the RipI features that contribute to its virulence activities identified two residues at the C-terminal domain that mediate RipI interaction with plant GADs and the subsequent promotion of GABA accumulation. These residues are also required for the appropriate homeostasis of RipI in plant cells and the induction of cell death, although they are partially dispensable for the suppression of plant immune responses. Altogether, we decipher and uncouple the virulence activities of an important bacterial effector at the biochemical level.


Assuntos
Proteínas de Bactérias , Morte Celular , Imunidade Vegetal , Ralstonia solanacearum , Ácido gama-Aminobutírico , Ralstonia solanacearum/patogenicidade , Ralstonia solanacearum/fisiologia , Ácido gama-Aminobutírico/metabolismo , Proteínas de Bactérias/metabolismo , Doenças das Plantas/microbiologia , Doenças das Plantas/imunologia , Nicotiana/microbiologia , Nicotiana/imunologia , Virulência , Proteínas de Plantas/metabolismo , Glutamato Descarboxilase/metabolismo , Homeostase
17.
Diabetes Metab Res Rev ; 40(3): e3758, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38103209

RESUMO

AIMS: Infections are proposed risk factors for type 1 diabetes in children. We examined whether a diagnosis of infectious disease also confers an increased risk of latent autoimmune diabetes in adults (LADA). MATERIALS AND METHODS: We used data from a population-based Swedish case-control study with incident cases of LADA (n = 597) and matched controls (n = 2386). The history of infectious disease was ascertained through national and regional patient registers. We estimated adjusted odds ratios (OR) with 95% confidence intervals for ≥1 respiratory (any/upper/lower), gastrointestinal, herpetic, other or any infectious disease episode, or separately, for 1 and ≥2 infectious disease episodes, within 0-1, 1-3, 3-5 and 5-10 years before LADA diagnosis/matching. Stratified analyses were performed on the basis of HLA risk genotypes and Glutamic acid decarboxylase antibodies (GADA) levels. RESULTS: Individuals who developed LADA did not have a higher prevalence of infectious disease 1-10 years before diabetes diagnosis. For example, OR was estimated at 0.87 (0.66, 1.14) for any versus no respiratory infectious disease within 1-3 years. Similar results were seen for LADA with high-risk HLA genotypes (OR 0.95 [0.64, 1.42]) or high GADA levels (OR 1.10 [0.79, 1.55]), ≥2 episodes (OR 0.89 [0.56, 1.40]), and in infections treated using antibiotics (OR 1.03 [0.73, 1.45]). The only significant association was observed with lower respiratory disease the year preceding LADA diagnosis (OR 1.67 [1.06, 2.64]). CONCLUSIONS: Our findings do not support the idea that exposure to infections increases the risk of LADA. A higher prevalence of respiratory infection in the year before LADA diagnosis could reflect increased susceptibility to infections due to hyperglycemia.


Assuntos
Doenças Transmissíveis , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Autoimune Latente em Adultos , Adulto , Criança , Humanos , Diabetes Autoimune Latente em Adultos/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/epidemiologia , Doenças Transmissíveis/complicações , Autoanticorpos , Glutamato Descarboxilase
18.
Diabet Med ; 41(9): e15394, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38937948

RESUMO

AIM: This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. METHODS: Pre-diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t-tests. RESULTS: Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody-positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA-positivity was higher in insulin-treated relatives than in non-insulin-treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA-positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody-positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). CONCLUSION: This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis.


Assuntos
Autoanticorpos , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Humanos , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Autoanticorpos/sangue , Masculino , Feminino , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/diagnóstico , Adulto , Pessoa de Meia-Idade , Criança , Ilhotas Pancreáticas/imunologia , Glutamato Descarboxilase/imunologia , Transportador 8 de Zinco/imunologia , Insulina/imunologia , Insulina/uso terapêutico , Adolescente , Família , Pré-Escolar , Predisposição Genética para Doença
19.
Epilepsia ; 65(10): e182-e189, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39110151

RESUMO

Epilepsy associated with high-titer glutamic acid decarboxylase 65 (GAD65) IgG is often refractory to immunotherapies and antiseizure medication. This study sought to determine the efficacy of vagus nerve stimulation (VNS) and surgical resection in patients with drug-resistant epilepsy associated with GAD65-IgG. We retrospectively identified 15 patients with drug-resistant epilepsy and high serum GAD65 antibody titers (>20 nmol·L-1) who underwent VNS implantation (n = 6), surgical resection (n = 7), or both (n = 2). A responder to VNS was defined as someone with a ≥50% reduction in seizure frequency, and a favorable surgical outcome was defined as Engel I-II. Of the eight patients who underwent VNS implantation, three (37.5%) were initially responders, but this was not sustained in two. Of the nine patients who underwent surgical resection, three (33.3%) had a favorable outcome; however, only one patient was seizure-free at last follow-up. Pathology was available in six patients, and only one had evidence of inflammation; this patient had seizure onset 1 year prior to surgery. Favorable seizure outcome correlated with older age at time of resective surgery, with a trend favoring later age of seizure onset. Taken together, surgical resection and VNS implantation may have limited efficacy in this patient population but can be considered in carefully selected cases.


Assuntos
Epilepsia Resistente a Medicamentos , Glutamato Descarboxilase , Estimulação do Nervo Vago , Humanos , Estimulação do Nervo Vago/métodos , Masculino , Feminino , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia Resistente a Medicamentos/terapia , Epilepsia Resistente a Medicamentos/imunologia , Glutamato Descarboxilase/imunologia , Adulto , Resultado do Tratamento , Estudos Retrospectivos , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Autoanticorpos/sangue , Criança
20.
Vox Sang ; 119(10): 1106-1110, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38955431

RESUMO

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulins (IVIgs) contain various autoantibodies, including those against glutamic acid decarboxylase (GADAb), a valuable biomarker of type 1 diabetes mellitus. Passive transfer of GADAb from IVIgs to patients poses a risk of misdiagnosis, and information on the specific titres of GADAb and their impact on diagnostic accuracy remains limited. This study aimed to provide further insights into the origin of GADAb detected in patient serum following IVIg infusion. MATERIALS AND METHODS: GADAb titres in IVIg products from Japan and the United States were measured using enzyme-linked immunosorbent assay-based assays. For reliable quantification, GADAb titres in pooled plasma were quantified and compared with those in the IVIg products. The determined titres were used to estimate the likelihood of passively detecting acquired GADAb in individuals receiving IVIgs. RESULTS: GADAbs were prevalent in IVIg products; however, the titres varied significantly among different lots and products. Importantly, IVIg-derived GADAb was estimated to remain detectable in patient serum for up to 100 days following a dosage of 2000 mg/kg. CONCLUSION: Clinicians should consider that IVIg preparations may contain GADAb, which can lead to false-positive results in serological assays. Careful interpretation of the assay results is key to the definitive diagnosis of type 1 diabetes mellitus.


Assuntos
Autoanticorpos , Diabetes Mellitus Tipo 1 , Glutamato Descarboxilase , Imunoglobulinas Intravenosas , Diabetes Mellitus Tipo 1/sangue , Humanos , Glutamato Descarboxilase/imunologia , Autoanticorpos/sangue , Masculino , Feminino , Japão , Ensaio de Imunoadsorção Enzimática/métodos
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