ABSTRACT
The SLC6A4 gene encodes the serotonin transporter SERT. Since the discovery of the role of SLC6A4 polymorphisms on human behavior, there is an increasingly growing wealth of information regarding SLC6A4 gene variants associated with anxiety and mood disorders, as well as their pharmacogenetic implications. In this brief review, the main discoveries on SLC6A4 variants, their functional impact and their suggested roles in neuropsychiatric and neurodevelopmental disorders are discussed.
El gen SLC6A4 codifica el transportador de serotonina SERT. Desde el descubrimiento inicial del rol que tienen polimorfismos de SLC6A4 en el comportamiento humano, hay una creciente cantidad de información acerca de variantes genéticas de SLC6A4 asociadas con trastornos de ansiedad y de estado de ánimo, así como de sus implicancias farmacogenéticas. En esta breve revisión, se discuten los principales descubrimientos de variantes de SLC6A4, su impacto funcional y sus roles sugeridos en enfermedades neuropsiquiátricas y de neurodesarrollo.
Subject(s)
Humans , Serotonin , Serotonin Plasma Membrane Transport Proteins , Nervous System DiseasesABSTRACT
Neuropsychiatric diseases (NPD) are characterized by changes in brain plasticity involving alterations in the morphology and functionality of neurons. However, affectations of the neuronal development (neurogenesis) in the adult brain are also shown. The neurogenic process is widely regulated by different factors such as genes, microenvironment, hormones, neurotransmitters, environmental cues and, also, nutrition. Thus, alterations in these factors negatively impact the neuronal development. Several studies performed in humans have revealed alterations of neurogenesis in NPD. However, most of the knowledge derives from studies done in animal models of NPD. The evidences from animal models are controversial, thus the use of human-induced pluripotent stem cells as a model of NPD has marked a way to study alterations in the neuronal development. Recently, the use of another cellular model for studying NPD has been proposed. Multipotent stem cells derived from olfactory epithelium (MOESCs) are a good candidate. However, evidences are scarce and deeper studies are necessary to know if there is or not a correlation of alterations in neuronal development in the OE with the changes observed in the brain; or if the MOESCs can mimic alterations shown in NPD that could let to get more knowledge about the factors promoting these diseases. Thus, in this review we discuss basic information about adult neurogenesis under physiological and non-physiological conditions in the hippocampus, olfactory bulb and olfactory epithelium.
Las enfermedades neuropsiquiátricas (ENP) se caracterizan por cambios en la plasticidad cerebral que incluyen la pérdida neuronal en regiones específicas en el encéfalo, cambios en la transmisión sináptica originada por alteraciones en los contactos sinápticos y también por la expresión de genes. Además, otro proceso que forma parte de la plasticidad cerebral y que también se encuentra afectado en las ENP es la generación de nuevas neuronas (neurogénesis). El proceso neurogénico en el adulto es regulado de manera fina por diversos factores como los aspectos genéticos, celulares, el microambiente, los elementos neuroquímicos, los ambientales y los nutricionales. Las alteraciones de estos factores impactan en el desarrollo y en la función de las nuevas neuronas. Algunos estudios realizados en humanos han revelado las alteraciones en la neurogénesis en algunos ENP. Sin embargo los mayores avances logrados han utilizado modelos animales de ENP. En algunos casos estas evidencias son controvertidas y recientemente se han tratado de aclarar utilizando cultivos de células madre pluripotenciales-inducibles humanas como modelos de ENP. Otro modelo que se ha propuesto para estudiar las alteraciones en el desarrollo neuronal en las ENP son las células madre multipotenciales del epitelio olfatorio (CMPEO). Sin embargo las evidencias obtenidas con las CMPEO son escasas y resulta necesario demostrar si existe o no un correlato con las alteraciones que ocurren en el desarrollo neuronal a nivel central en las ENP, o bien si las CMPEO pueden mostrar las alteraciones observadas en las ENP que permitan obtener información acerca de los factores que promueven estas enfermedades. Por lo tanto en esta revisión se incluyen aspectos básicos de la neurogénesis e información relevante de las alteraciones de este proceso en las tres regiones neurogénicas en el adulto: el hipocampo, el bulbo olfatorio y el epitelio olfatorio.
ABSTRACT
Circadian rhythms are oscillations of physiological functions. The period of their oscillation is about 24 h, and can be synchronized by environmental periodic signals as night-day cycle. The endogenous periodical changes depend on various structural elements of the circadian system which consists of the effectors, the secondary oscillators, the synchronizers and the circadian pacemaker. In mammalian species, the physiological function better understood respect their oscillation pattern are the synthesis and release of several hormones (i.e. cortisol and melatonin), the body temperature, the sleep-awake cycle, the locomotive activity, cell proliferation, neuronal activity among other rhythms. The Suprachiasmatic nucleus is the main circadian pacemarker in mammals; its oscillation keeps the circadian system synchronized particularly with respect to the environment photo period. When light reaches the pigment melanopsin in ganglionar neurons in the retina, the photoperiod signal is sent to Suprachiasmatic nucleus, and its postsinaptic neurons distributes the temporal signal to pheripheral oscillators by nervous or humoral pathways. Among the oscillators, the pineal gland is a peripheral one modulated by Suprachiasmatic nucleus. At night, the indolamine melatonin is synthesized and released from pinealocytes, and reaches other peripheral oscillators. Melatonin interacts with membrane receptors on Suprachiasmatic nucleus pacemarker neurons, reinforcing the signal of the photoperiod. In mammals, exogenous melatonin synchronizes several circadian rhythms including locomotive activity and melatonin release. When this indolamine is applied directly into the Suprachiasmatic nucleus, it produces a phase advance of the endogenous melatonin peak and increases the amplitude of the oscillation. In humans, melatonin effect on the circadian system is evident because it changes the circadian rhythms phase in subjects with advanced sleep-phase syndrome, night workers or blind people. Also it reduces jet lag symptoms enhancing sleep quality and reseting the circadian system to local time. Melatonin effects on circadian rhythms indicate their role as a chronobiotic, since decreased daily melatonin levels that occur with age and in neuropsychiatric disorders are associated with disturbances in the sleep-awake cycle. In particular, it has been described that Alzheimer's disease patients have disturbed sleep-awake cycle and have decreased serum melatonin levels. Sleep disorders in Alzheimer's disease patients decrease when they are treated with melatonin. Moreover, sleep disturbances have been observed in bipolar disorder patients and often precede relapses of insomnia-associated mania and hypersomnia-associated depression. These disturbances are linked to delayed- and advanced- phases of circadian rhythms or arrhythmia; therefore, it has been suggested that bipolar disorder patients could be treated with light and dark therapy. In depressed patients, the levels of melatonin are low throughout the 24 hour period and have a delayed onset of the indolamine concentration and showed an advance of its peak. Schizophrenic patients have decreased levels in the plasmatic melatonin in both phases of the light-dark cycle. Melatonin administration to these patients increases their sleep efficiency. In addition, melatonin acts as a neuroprotector because of its potent antioxidant action and through its cytoskeletal modulation properties. In neurodegenerative animal models, its protector effect has been observed using okadaic acid. This neurotoxin is employed for reproducing cytoskeletal damage in neurons and increased oxidative stress levels, which are molecular events similar to those that occur in Alzheimer's disease. In N1E-115 cell cultures incubated with okadaic acid, the administration of melatonin diminishes hyperphosphorylated tau and oxidative stress levels, and prevents the neurocytoskeletal damage caused by the neurotoxin. Although it is known that melatonin plays a key role in the circadian rhythms entrainment, little is known about its synchronizing effects at molecular and structural level. In algae, it has been observed a link between morphological changes and the light-dark cycle and it is known that shape is determinated by the cytoskeletal structure. In particular, the alga Euglena gracilis changes its shape two times per day under the effect of a daily light-dark cycle. This alga has a long shape when there is a higher photosynthetic capacity at the half period of the day; on the contrary, it showed a rounded shape at the end of 24 h cycle. Also, the influence of the cell shape changes on the photosynthetic reactions was investigated by altering them with drugs that disrupt the cytoskeletal structure as cytochalasin B and colchicine. Both inhibitors blocked the rhythmic shape changes and the photo-synthetic rhythm. Moreover, there are some reports about cytoskeletal changes in plants targeted by circadian rhythms. Guarda cells of Vicia faba L. showed a diurnal cycle on the alpha and beta tubulin levels. In addition, it has been proposed that melatonin synchronizes different body rhythms through cytoskeletal rearrangements. In culture cells, nanomolar melatonin concentrations cause an increase in both the polimerization rate and microtubule formation through calmodulin antagonism. A cyclic pattern produced by melatonin in the actin microfilament organization has been demonstrated in canine kidney cells. Cyclic incubation of MDCK cells with nanomolar concentrations of melatonin, resembling the cyclic pattern of secretion and release to plasma produces a microfilament reorganization and the formation of domes. Studies in animals are controvertial regarding if the amount of microtubules in different tissues varies cyclically. In rats and baboons, melatonin administration or exposure of rats to darkness induced an increased number of microtubules in the pineal gland. However, in the hypothalamus, the exposure of rats to light resulted in an increase in the microtubular protein content. Similarly, (X-tubulin mRNA was augmented during the light phase in the hypothalamus, hippocampus and cortex. By contrast, in rats maintained in constant darkness, a decreased level in the tubulin content was observed in the visual cortex. Additional information on cycle variations observed in cytoskeletal molecules indicated that beta actin mRNA levels are lower during the day in the hippocampus and cortex. But no change was observed in actin protein levels in the cerebral cortex. However, increased levels of actin and its mRNA were observed in the hypothalamus. Exogenous melatonin administration at onset of night decreased the amount of actin in the hypothalamus, while the actin mRNA levels decreased when the administration was realized in the morning. In this review we will describe the synchronizer role of melatonin in the sleep-awake cycle and in the organization of cytoskeletal proteins and their mRNAs. Also, we will describe alterations in the melatonin secretion rhythm associated with a neuronal cytoskeleton disorganization in the neuropsychiatric diseases such as Alzheimer, depression, bipolar disorder and schizophrenia.
Los ritmos circadianos son patrones de oscilación con un periodo cercano a 24h que se observan en los procesos fisiológicos. En los mamíferos se han descrito funciones biológicas con regulación circádica tal como el ciclo sueño-vigilia. La administración de la melatonina, una indolamina secretada por la glándula pineal, sincroniza los ritmos circadianos. En los humanos, este efecto se ha estudiado en sujetos con síndrome de <
ABSTRACT
Objetivo: Identificar factores de riesgo, genéticos, clínicos y ambientales, para el desarrollo de demencias, movimientos anormales y trastornos afectivos, en población adulta mayor de tres barrios de la Localidad Cuarta de Bogotá. Metodología: Estudio Piloto, analítico de tipo transversal, diseñado para la identificación clínica y de factores de riesgo en una muestra intencional con participación voluntaria de 250 individuos, realizado en dos etapas: primera, de tamización, con base en diagnóstico interdisciplinario (Medicina, Enfermería y Psicología); segunda, de confirmación diagnóstica por especialistas (Neurología y Psiquiatría). Diferentes instrumentos neuropsicológicos, pruebas de genética molecular y bioquímicas fueron realizadas a los participantes. Resultados: Se estudiaron individuos de ambos sexos con edad promedio de 68,3 años, y algunos de sus familiares. El 65,5% de la población de estudio está afectada por alguna de las entidades valoradas, con una mayor frecuencia de los trastornos afectivos (35,0%), seguida por alteración de las funciones cognitivas (23,3%). Los estudios genéticos permitieron identificar varios polimorfismos en genes que pueden estar influyendo en la aparición de estas enfermedades. Conclusiones: Estudio poblacional interdisciplinario en una de las localidades de Bogotá, D.C de estratos uno y dos para identificar trastornos cognitivos, afectivos y de movimientos anormales, con instrumentos clínicos y de biología molecular, lo que permite avanzar en la caracterización de perfiles genéticos de nuestra población y sus aplicaciones en programas de Salud Pública.
Objective:To identify genetic, clinical, and environmental risk factors for the development of dementias, abnormal movements, and affective disorders in the senior citizen population of three neighborhoods in Bogotás Fourth Locality.Methodology: Pilot Study, transversal analytic, designed for the identification of clinical and risk factors in an intentional sample with the voluntary participation of 250 individuals, realized in two stages: first sifting, based in interdisciplinary diagnostics (Medicine, Nursing, Psychology); second, diagnostic confirmation by specialists (Neurology and Psychiatry). Different neuropsychological instruments, molecular and biochemical genetic tests were used on the participants.Results Individuals of both sexes with an pproximate age of 68.3 years were studied, and some of their relatives. 65.5% of the study population is affected by some of the valued entities, with the greatest frequency of affective disorders (35,0%), followed by alteration of the cognitive functions (23,3%). The genetic studies identified various polymorphisms in genes that could be influencing the appearance of these illnesses.Conclusions Populational interdisciplinary study in one of the localities of Bogotá, D.C. in two stages to identify cognitive and affective disorders and abnormal movements, with clinical instruments and molecular biology, which permits an advance in the characterization of genetic profiles for our population and their application in Public Health programs.Key wordsMental health, neuropsychiatric illness, senior citizen, genetic factors, environmental factors, Public Health.