RESUMEN
The olfactory system is renowned for its functional and structural plasticity, with both peripheral and central structures displaying persistent neurogenesis throughout life and exhibiting remarkable capacity for regenerative neurogenesis after damage. In general, fish are known for their extensive neurogenic ability, and the zebrafish in particular presents an attractive model to study plasticity and adult neurogenesis in the olfactory system because of its conserved structure, relative simplicity, rapid cell turnover, and preponderance of neurogenic niches. In this review, we present an overview of the anatomy of zebrafish olfactory structures, with a focus on the neurogenic niches in the olfactory epithelium, olfactory bulb, and ventral telencephalon. Constitutive and regenerative neurogenesis in both the peripheral olfactory organ and central olfactory bulb of zebrafish is reviewed in detail, and a summary of current knowledge about the cellular origin and molecular signals involved in regulating these processes is presented. While some features of physiologic and injury-induced neurogenic responses are similar, there are differences that indicate that regeneration is not simply a reiteration of the constitutive proliferation process. We provide comparisons to mammalian neurogenesis that reveal similarities and differences between species. Finally, we present a number of open questions that remain to be answered.
Asunto(s)
Neurogénesis/fisiología , Receptores Odorantes/fisiología , Animales , Pez CebraRESUMEN
The olfactory system, composed of the olfactory organs and the olfactory bulb, allows organisms to interact with their environment and through the detection of odor signals. Olfaction mediates behaviors pivotal for survival, such as feeding, mating, social behavior, and danger assessment. The olfactory organs are directly exposed to the milieu, and thus are particularly vulnerable to damage by environmental pollutants and toxicants, such as heavy metals, pesticides, and surfactants, among others. Given the widespread occurrence of olfactory toxicants, there is a pressing need to understand the effects of these harmful compounds on olfactory function. Zebrafish (Danio rerio) is a valuable model for studying human physiology, disease, and toxicity. Additionally, the anatomical components of the zebrafish olfactory system are similar to those of other vertebrates, and they present a remarkable degree of regeneration and neuroplasticity, making it an ideal model for the study of regeneration, reorganization and repair mechanisms following olfactory toxicant exposure. In this review, we focus on (1) the anatomical, morphological, and functional organization of the olfactory system of zebrafish; (2) the adverse effects of olfactory toxicants and injury to the olfactory organ; and (3) remodeling and repair neuroplasticity mechanisms following injury and degeneration by olfactory toxicant exposure.
Asunto(s)
Modelos Animales de Enfermedad , Plasticidad Neuronal , Síndromes de Neurotoxicidad/fisiopatología , Bulbo Olfatorio/lesiones , Pez Cebra/fisiología , Animales , Odorantes , Bulbo Olfatorio/patologíaRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficient social interaction, impaired communication as well as repetitive behaviors. ASD subjects present connectivity and neuroplasticity disturbances associated with morphological alterations in axons, dendrites, and dendritic spines. Given that the neuronal cytoskeleton and astrocytes have an essential role in regulating several mechanisms of neural plasticity, the aim of this work was to study alterations in the content of neuronal cytoskeletal components actin and tubulin and their associated proteins, as well as astrocytic proteins GFAP and TSP-1 in the brain of a C58/J mouse model of ASD. We determined the expression and regulatory phosphorylation state of cytoskeletal components in the prefrontal cortex, hippocampus, and cerebellum of C58/J mice by means of Western blotting. Our results show that autistic-like mice present: 1) region-dependent altered expression and phosphorylation patterns of Tau isoforms, associated with anomalous microtubule depolymerization; 2) reduced MAP2â¯A content in prefrontal cortex; 3) region-dependent changes in cofilin expression and phosphorylation, associated with abnormal actin filament depolymerizing dynamics; 4) diminished synaptopodin levels in the hippocampus; and 5) reduced content of the astrocyte-secreted protein TSP-1 in the prefrontal cortex and hippocampus. Our work demonstrates changes in the expression and phosphorylation of cytoskeletal proteins as well as in TSP-1 in the brain of the autistic-like mice C58/J, shedding light in one of the possible molecular mechanisms underpinning neuroplasticity alterations in the ASD brain and laying the foundation for future investigations in this topic.
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Astrocitos/metabolismo , Trastorno Autístico/metabolismo , Encéfalo/metabolismo , Proteínas del Citoesqueleto/metabolismo , Neuronas/metabolismo , Trombospondina 1/metabolismo , Animales , Trastorno Autístico/genética , Citoesqueleto/genética , Citoesqueleto/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trombospondina 1/genéticaRESUMEN
The high consumption of saturated lipids has been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance in peripheral tissues. However, how neurons develop insulin resistance in response to lipid overload is not fully understood. Here, we used cultured rat cortical neurons and differentiated human neuroblastoma cells to demonstrate that PA blocks insulin-induced metabolic activation, inhibits the activation of the insulin/PI3K/Akt pathway and activates mTOR kinase downstream of Akt. Despite the fact that fatty acids are not normally used as a significant source of fuel by neural cells, we also found that short-term neuronal exposure to PA reduces the NAD+/NADH ratio, indicating that PA modifies the neuronal energy balance. Finally, inhibiting mitochondrial ROS production with mitoTEMPO prevented the deleterious effect of PA on insulin signaling. This work provides novel evidence of the mechanisms behind saturated fatty acid-induced insulin resistance and its metabolic consequences on neuronal cells.
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Insulina/metabolismo , Ácido Palmítico/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Línea Celular Tumoral , Células Cultivadas , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Humanos , Antagonistas de Insulina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuroblastoma/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Ratas , Transducción de SeñalRESUMEN
NMDA receptors (NMDARs) are key mediators of glutamatergic transmission and synaptic plasticity, and their dysregulation has been linked to diverse neuropsychiatric and neurodegenerative disorders. While normal NMDAR function requires regulated expression and trafficking of its different subunits, the molecular mechanisms underlying these processes are not fully understood. Here we report that the amyloid precursor protein intracellular domain associated-1 protein (AIDA-1), which associates with NMDARs and is encoded by ANKS1B, a gene recently linked to schizophrenia, regulates synaptic NMDAR subunit composition. Forebrain-specific AIDA-1 conditional knock-out (cKO) mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission, and biochemical analyses show AIDA-1 cKO mice have low GluN2B and high GluN2A protein levels at isolated hippocampal synaptic junctions compared with controls. These results are corroborated by immunocytochemical and electrophysiological analyses in primary neuronal cultures following acute lentiviral shRNA-mediated knockdown of AIDA-1. Moreover, hippocampal NMDAR-dependent but not metabotropic glutamate receptor-dependent plasticity is impaired in AIDA-1 cKO mice, further supporting a role for AIDA-1 in synaptic NMDAR function. We also demonstrate that AIDA-1 preferentially associates with GluN2B and with the adaptor protein Ca(2+)/calmodulin-dependent serine protein kinase and kinesin KIF17, which regulate the transport of GluN2B-containing NMDARs from the endoplasmic reticulum (ER) to synapses. Consistent with this function, GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice. These findings suggest that AIDA-1 regulates NMDAR subunit composition at synapses by facilitating transport of GluN2B from the ER to synapses, which is critical for NMDAR plasticity. Our work provides an explanation for how AIDA-1 dysfunction might contribute to neuropsychiatric conditions, such as schizophrenia.
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Proteínas Portadoras/fisiología , Hipocampo/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , Células Cultivadas , Retículo Endoplásmico/química , Retículo Endoplásmico/fisiología , Femenino , Hipocampo/química , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Subunidades de Proteína/análisis , Subunidades de Proteína/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/análisis , Sinapsis/químicaRESUMEN
A growing body of animal and epidemiological studies suggest that metabolic diseases such as obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus are associated with the development of cognitive impairment, dementia and Alzheimer's disease, particularly in aging. Several lines of evidence suggest that insulin signalling dysfunction produces these metabolic alterations and underlie the development of these neurodegenerative diseases. In this article, we address normal insulin function in the synapse; we review and discuss the physiopathological hallmarks of synaptic insulin signalling dysfunction associated with metabolic alterations. Additionally, we describe and review the major animal models of obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus. The comprehensive knowledge of the molecular mechanisms behind the association of metabolic alterations and cognitive impairment could facilitate the early detection of neurodegenerative diseases in patients with metabolic alterations, with treatment that focus on neuroprotection. It could also help in the development of metabolic-based therapies and drugs for using in dementia and Alzheimer's disease patients to alleviate their symptoms in a more efficient and comprehensive way.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Trastornos del Conocimiento/etiología , Hipocampo/metabolismo , Hipocampo/patología , Insulina/metabolismo , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/patología , Animales , Cognición/efectos de los fármacos , Cognición/fisiología , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Humanos , Insulina/farmacología , Obesidad/complicaciones , Obesidad/epidemiología , Transducción de Señal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/metabolismoRESUMEN
Chronic consumption of high-fat-and-fructose diets (HFFD) is associated with the development of insulin resistance (InsRes) and obesity. Systemic insulin resistance resulting from long-term HFFD feeding has detrimental consequences on cognitive performance, neurogenesis, and long-term potentiation establishment, accompanied by neuronal alterations in the hippocampus. However, diet-induced hippocampal InsRes has not been reported. Therefore, we investigated whether short-term HFFD feeding produced hippocampal insulin signaling alterations associated with neuronal changes in the hippocampus. Rats were fed with a control diet or an HFFD consisting of 10% lard supplemented chow and 20% high-fructose syrup in the drinking water. Our results show that 7 days of HFFD feeding induce obesity and InsRes, associated with the following alterations in the hippocampus: (1) a decreased insulin signaling; (2) a decreased hippocampal weight; (3) a reduction in dendritic arborization in CA1 and microtubule-associated protein 2 (MAP-2) levels; (4) a decreased dendritic spine number in CA1 and synaptophysin content, along with an increase in tau phosphorylation; and finally, (5) an increase in reactive astrocyte associated with microglial changes. To our knowledge, this is the first report addressing hippocampal insulin signaling, as well as morphologic, structural, and functional modifications due to short-term HFFD feeding in the rat.
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Astrocitos/metabolismo , Grasas de la Dieta/efectos adversos , Fructosa/efectos adversos , Hipocampo/metabolismo , Resistencia a la Insulina , Insulina/metabolismo , Neuritas/metabolismo , Transducción de Señal/efectos de los fármacos , Edulcorantes/efectos adversos , Sinapsis/metabolismo , Animales , Astrocitos/patología , Grasas de la Dieta/farmacocinética , Fructosa/farmacología , Hipocampo/patología , Masculino , Neuritas/patología , Ratas , Ratas Sprague-Dawley , Edulcorantes/farmacología , Sinapsis/patologíaRESUMEN
Human alpha(1D)-adrenoceptors (truncated at the amino terminus (Delta1-79) to increase their membrane expression) were stably expressed in Rat-1 fibroblasts (1-1.5 pmol/mg protein). The receptors were functional as evidenced by a robust increase in intracellular calcium in response to noradrenaline. Using this cell line, the possibility that activation of receptor tyrosine kinases could modulate this adrenoceptor subtype was studied. It was observed that cell preincubation with insulin, IGF-I, EGF or PDGF markedly reduced the intracellular calcium increase observed in response to noradrenaline. Inhibitors of PI3K and PKC essentially blocked insulin-, IGF-I- and EGF-induced desensitizations. Interestingly, PDGF-induced alpha(1D)-adrenergic desensitization was only partially ameliorated by PI3K inhibitors and was not affected by those of PKC. Insulin, IGF-I, EGF and PDGF induced concentration-dependent increases in the phosphorylation state of alpha(1D)-adrenoceptors; phosphorylation took place on serine residues. Inhibitors of PI3K and PKC markedly reduced the effects of insulin, IGF-I and EGF on this parameter. These inhibitors only marginally reduced PDGF-induced alpha(1D)-adrenoceptors phosphorylation. The ability of IGF-I to induce alpha(1D)-adrenergic desensitization and phosphorylation was confirmed in cells expressing non-truncated rat alpha(1D)-adrenoceptors. Our data indicate that the function and phosphorylation state of alpha(1D)-adrenoceptors is modulated by activation of receptor tyrosine kinases. Insulin, IGF-I and EGF actions take place through the action of PI3K and PKC; additional pathway(s) seem to participate in PDGF-induced alpha(1D)-adrenoceptor desensitization and phosphorylation.