RESUMO
Fipronil, a pesticide widely used to control agricultural and household insect pests, blocks insect GABAA and glutamate (GluCl) ionotropic receptors, resulting in uncontrolled hyperexcitation and paralysis that eventually leads to death. The use of fipronil is controversial because unintentional exposure to this compound may contribute to the ongoing global decline of insect pollinator populations. Although the sublethal effects of fipronil have been linked to aberrant behavior and impaired olfactory learning in insects, the precise mechanisms involved in these responses remain unclear. In this article, we highlight recent studies that have investigated the interaction among different pathways involved in the ability of fipronil to modulate insect behavior, with particular emphasis on the role of GABAergic neurotransmission in fine-tuning the integration of sensorial responses and insect behavior. Recent findings suggest that fipronil can also cause functional alterations that affect synaptic organization and the availability of metal ions in the brain.
Assuntos
Comportamento Animal , Insetos , Inseticidas , Pirazóis , Animais , Pirazóis/toxicidade , Insetos/efeitos dos fármacos , Insetos/fisiologia , Inseticidas/toxicidade , Comportamento Animal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacosRESUMO
Aging is characterized by the decline in many of the individual's capabilities. It has been recognized that the brain undergoes structural and functional changes during aging that are occasionally associated with the development of neurodegenerative diseases. In this sense, altered glutamatergic neurotransmission, which involves the release, binding, reuptake, and degradation of glutamate (Glu) in the brain, has been widely studied in physiological and pathophysiological aging. In particular, changes in glutamatergic neurotransmission are exacerbated during neurodegenerative diseases and are associated with cognitive impairment, characterized by difficulties in memory, learning, concentration, and decision-making. Thus, in the present manuscript, we aim to highlight the relevance of glutamatergic neurotransmission during cognitive impairment to develop novel strategies to prevent, ameliorate, or delay cognitive decline. To achieve this goal, we provide a comprehensive review of the changes reported in glutamatergic neurotransmission components, such as Glu transporters and receptors during physiological aging and in the most studied neurodegenerative diseases. Finally, we describe the current therapeutic strategies developed to target glutamatergic neurotransmission.
Assuntos
Envelhecimento , Disfunção Cognitiva , Ácido Glutâmico , Doenças Neurodegenerativas , Transmissão Sináptica , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Ácido Glutâmico/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologiaRESUMO
Omega-3 (n3) is a polyunsaturated fatty acid well known for its anti-inflammatory and neuroprotective properties. Obesity is linked to chronic inflammation that disrupts metabolism, the intestine physiology and the central nervous system functioning. This study aims to determine if n3 supplementation can interfere with the effects of obesity on the mitochondrial activity, intestinal barrier, and neurotransmitter levels in the brain of Wistar rats that received cafeteria diet (CAF). We examined adipose tissue, skeletal muscle, plasma, intestine, and the cerebral cortex of four groups: CT (control diet), CTn3 (control diet with n3 supplementation), CAF, and CAFn3 (CAF and n3). Diets were offered for 13 weeks, with n3 supplementation in the final 5 weeks. Adipose tissue Electron Transport Chain complexes I, II, and III showed higher activity in CAF groups, as did complexes III and IV in skeletal muscle. Acetate levels in plasma were reduced in CAF groups, and Lipopolysaccharide (LPS) was higher in the CAF group but reduced in CAFn3 group. Claudin-5 in the intestine was lower in CAF groups, with no n3 supplementation effect. In the cerebral cortex, dopamine levels were decreased with CAF, which was reversed by n3. DOPAC, a dopamine metabolite, also showed a supplementation effect, and HVA, a diet effect. Serotonin levels increased in the CAF group that received supplementation. Therefore, we demonstrate disturbances in mitochondria, plasma, intestine and brain of rats submitted to CAF and the potential benefit of n3 supplementation in endotoxemia and neurotransmitter levels.
Assuntos
Ácidos Graxos Ômega-3 , Obesidade , Ratos Wistar , Transmissão Sináptica , Animais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Obesidade/metabolismo , Masculino , Transmissão Sináptica/efeitos dos fármacos , Ratos , Suplementos Nutricionais , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacosRESUMO
Childhood obesity increases the risk of health and cognitive disorders in adulthood. Consuming high-fat diets (HFD) during critical neurodevelopmental periods, like childhood, impairs cognition and memory in humans and animals, affecting the function and connectivity of brain structures related to emotional memory. However, the underlying mechanisms of such phenomena need to be better understood. This study aimed to investigate the neurochemical profile of the amygdala and hippocampus, brain structures involved in emotional memory, during the acquisition of conditioned odor aversion in male rats that consumed a HFD from weaning to adulthood. The rats gained weight, experienced metabolic changes, and reduced insulin sensitivity and glucose tolerance. Rats showed enhanced odor aversion memory, contrary to the expected cognitive impairments. This memory enhancement was accompanied by increased noradrenergic and glutamatergic neurotransmission in the amygdala and hippocampus. Importantly, this upregulation was specific to stimuli exposure, as basal neurotransmitter levels remained unaltered by the HFD. Our results suggest that HFD modifies cognitive function by altering neurochemical signaling, in this case, upregulating neurotransmitter levels rendering a stronger memory trace, demonstrating that metabolic dysfunctions do not only trigger exclusively detrimental plasticity processes but also render enhanced plastic effects depending on the type of information.
Assuntos
Tonsila do Cerebelo , Dieta Hiperlipídica , Ácido Glutâmico , Hipocampo , Transmissão Sináptica , Animais , Masculino , Dieta Hiperlipídica/efeitos adversos , Hipocampo/metabolismo , Tonsila do Cerebelo/metabolismo , Transmissão Sináptica/fisiologia , Ratos , Ácido Glutâmico/metabolismo , Norepinefrina/metabolismo , Ratos Wistar , Cognição/fisiologia , Aprendizagem da Esquiva/fisiologiaRESUMO
BACKGROUND: Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K+ stimulation in brain slices. RESULTS: Focal high-K+ stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K+-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus. CONCLUSIONS: Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries.
Assuntos
Astrócitos , Conexina 43 , Conexinas , Depressão Alastrante da Atividade Elétrica Cortical , Transmissão Sináptica , Animais , Astrócitos/fisiologia , Conexinas/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Conexina 43/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Córtex Cerebral , Neurônios/fisiologia , Hipocampo , Ratos Sprague-Dawley , Ratos , Potássio/metabolismoRESUMO
BACKGROUND: The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown. RESULTS: To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments. CONCLUSIONS: We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions.
Assuntos
Camundongos Knockout , Vesículas Sinápticas , Animais , Camundongos , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Sinapses/metabolismo , Sinapses/fisiologia , Transmissão Sináptica , Vesículas Sinápticas/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
BACKGROUND: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRß in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. RESULTS: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. CONCLUSIONS: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.
Assuntos
Transtorno Autístico , Neurônios , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores , Animais , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Camundongos , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Modelos Animais de Doenças , Masculino , Córtex Cerebral/metabolismo , Camundongos Knockout , Transmissão Sináptica/fisiologia , Camundongos Endogâmicos C57BL , FemininoRESUMO
Transient or partial synchronization can be used to do computations, although a fully synchronized network is sometimes related to the onset of epileptic seizures. Here, we propose a homeostatic mechanism that is capable of maintaining a neuronal network at the edge of a synchronization transition, thereby avoiding the harmful consequences of a fully synchronized network. We model neurons by maps since they are dynamically richer than integrate-and-fire models and more computationally efficient than conductance-based approaches. We first describe the synchronization phase transition of a dense network of neurons with different tonic spiking frequencies coupled by gap junctions. We show that at the transition critical point, inputs optimally reverberate through the network activity through transient synchronization. Then, we introduce a local homeostatic dynamic in the synaptic coupling and show that it produces a robust self-organization toward the edge of this phase transition. We discuss the potential biological consequences of this self-organization process, such as its relation to the Brain Criticality hypothesis, its input processing capacity, and how its malfunction could lead to pathological synchronization and the onset of seizure-like activity.
Assuntos
Homeostase , Modelos Neurológicos , Rede Nervosa , Neurônios , Homeostase/fisiologia , Neurônios/fisiologia , Rede Nervosa/fisiologia , Humanos , Potenciais de Ação/fisiologia , Animais , Simulação por Computador , Encéfalo/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
Circular RNAs (circRNAs) are a large class of noncoding RNAs. Despite the identification of thousands of circular transcripts, the biological significance of most of them remains unexplored, partly because of the lack of effective methods for generating loss-of-function animal models. In this study, we focused on circTulp4, an abundant circRNA derived from the Tulp4 gene that is enriched in the brain and synaptic compartments. By creating a circTulp4-deficient mouse model, in which we mutated the splice acceptor site responsible for generating circTulp4 without affecting the linear mRNA or protein levels, we were able to conduct a comprehensive phenotypic analysis. Our results demonstrate that circTulp4 is critical in regulating neuronal and brain physiology, modulating the strength of excitatory neurotransmission and sensitivity to aversive stimuli. This study provides evidence that circRNAs can regulate biologically relevant functions in neurons, with modulatory effects at multiple levels of the phenotype, establishing a proof of principle for the regulatory role of circRNAs in neural processes.
Assuntos
Encéfalo , RNA Circular , Transmissão Sináptica , RNA Circular/genética , Animais , Camundongos , Encéfalo/metabolismo , Encéfalo/fisiologia , Camundongos Knockout , Neurônios/metabolismo , Neurônios/fisiologiaRESUMO
Circadian rhythms synchronize to light through the retinohypothalamic tract (RHT), which is a bundle of axons coming from melanopsin retinal ganglion cells, whose synaptic terminals release glutamate to the ventral suprachiasmatic nucleus (SCN). Activation of AMPA-kainate and NMDA postsynaptic receptors elicits the increase in intracellular calcium required for triggering the signaling cascade that ends in phase shifts. During aging, there is a decline in the synchronization of circadian rhythms to light. With electrophysiological (whole-cell patch-clamp) and immunohistochemical assays, in this work, we studied pre- and postsynaptic properties between the RHT and ventral SCN neurons in young adult (P90-120) and old (P540-650) C57BL/6J mice. Incremental stimulation intensities (applied on the optic chiasm) induced much lesser AMPA-kainate postsynaptic responses in old animals, implying a lower recruitment of RHT fibers. Conversely, a higher proportion of old SCN neurons exhibited synaptic facilitation, and variance-mean analysis indicated an increase in the probability of release in RHT terminals. Moreover, both spontaneous and miniature postsynaptic events displayed larger amplitudes in neurons from aged mice, whereas analysis of the NMDA and AMPA-kainate components (evoked by RHT electrical stimulation) disclosed no difference between the two ages studied. Immunohistochemistry revealed a bigger size in the puncta of vGluT2, GluN2B, and GluN2A of elderly animals, and the number of immunopositive particles was increased, but that of PSD-95 was reduced. All these synaptic adaptations could be part of compensatory mechanisms in the glutamatergic signaling to ameliorate the loss of RHT terminals in old animals.