RESUMEN
Since the discovery in 2001, the G protein-coupled trace amine-associated receptor 1 (TAAR1) has become an important focus of research targeted on evaluation of its role in the central nervous system (CNS). Meanwhile, impact of TAAR1 in the peripheral organs is less investigated. Expression of TAAR1 was demonstrated in different peripheral tissues: pancreatic ß-cells, stomach, intestines, white blood cells (WBC), and thyroid. However, the role of TAAR1 in regulation of hematological parameters has not been investigated yet. In this study, we performed analysis of anxiety-related behaviors, a complete blood count (CBC), erythrocyte fragility, as well as FT3/FT4 thyroid hormones levels in adult and middle-aged TAAR1 knockout mice. Complete blood count analysis was performed on a Siemens Advia 2120i hematology analyzer and included more than 35 measured and calculated parameters. Erythrocyte fragility test evaluated spherocytosis pathologies of red blood cells (RBC). No significant alterations in essentially all these parameters were found in mice without TAAR1. However, comparative aging analysis has revealed a decreased neutrophils level in the middle-aged TAAR1 knockout mouse group. Minimal alterations in these parameters observed in TAAR1 knockout mice suggest that future TAAR1-based therapies should exert little hematological effect and thus will likely have a good safety profile.
Asunto(s)
Ansiedad/sangre , Receptores Acoplados a Proteínas G/sangre , Receptores Acoplados a Proteínas G/deficiencia , Factores de Edad , Animales , Ansiedad/psicología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Cloruro de Sodio/toxicidadRESUMEN
Huntington's disease is a hereditary neurodegenerative disease that primarily affects striatal neurons. Recent studies demonstrated abnormalities in calcium regulation in striatal neurons in Huntington's disease, which leads to elimination of synaptic connections between cortical and striatal neurons. In the present study, we focused on the neuroprotective properties of σ1-receptor, because one of its main functions is associated with modulation of calcium homeostasis in cells. The application of selective σ1-receptor agonists to the corticostriatal cell culture restores synaptic connections between the cortical and striatal neurons. Based on the obtained data, we assume that σ1-receptor is a promising target for the development of drugs for the therapy of Huntington's disease.
Asunto(s)
Calcio/metabolismo , Enfermedad de Huntington/genética , Neuronas/metabolismo , Receptores sigma/genética , Transmisión Sináptica/genética , Animales , Anisoles/farmacología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Cuerpo Estriado/metabolismo , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Expresión Génica , Homeostasis , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Masculino , Ratones , Modelos Biológicos , Morfolinas/farmacología , Neuronas/patología , Piperidinas/farmacología , Cultivo Primario de Células , Propilaminas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores sigma/agonistas , Receptores sigma/antagonistas & inhibidores , Receptores sigma/metabolismo , Sinapsis/metabolismo , Sinapsis/patología , Transducción Genética , Receptor Sigma-1RESUMEN
The effect of CyPPA, a positive modulator of small conductance calcium-activated potassium channels of type 3 and 2 (SK3/SK2), and of NS309, an activator of intermediate and small conductance calcium-activated potassium channels (IK/SK), on the activity of cerebellar Purkinje cells was studied in 2-month-old male mice. The use of 1 mM of CyPPA has led to a decrease of simple spike firing frequency in the discharge of Purkinje cells by 25%, on average, during 1 h after application. At the same time, application of 100 µM of NS309 has promoted a decrease in simple spike firing frequency by 47 %, on average, during 1 h after the beginning of the action. The obtained results confirm the hypothesis that SK channels participate in regulation of simple spike firing frequency in the discharge of Purkinje cells and are responsible for restriction of signal frequency. The effect of NS309 on simple spike firing frequency was more pronounced; therefore, the IK/SK channels may be suggested to play the cardinal role in regulation of spike activity of Purkinje cells. Since increasing simple spike frequency in the discharge of Purkinje cells is observed at many disturbances of motor activity, in particular, at spinocerebellar ataxia, it can be suggested that the studied compounds or substances of similar action are of interest as potential medicinal agents.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Células de Purkinje/fisiología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Animales , Indoles/farmacología , Masculino , Ratones , Oximas/farmacología , Células de Purkinje/metabolismo , Pirazoles/farmacología , Pirimidinas/farmacología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/agonistasRESUMEN
Optogenetics is a modern nanobiological approaches allowing modulation of the physiological status of electrostimulated cells, including the neurons. The optogenetic approach was used to evaluate the efficiency of synaptic transmission between the neurons in a mixed corticostriatal culture. Synaptic contacts between the cortical and striatal neurons forming in a mixed culture could be modulated by the opticogenetic methods. Studies of the synaptic interactions between the neurons were essential for understanding the disease mechanisms, and therefore, this method seemed to be promising for biomedical studies.
Asunto(s)
Neuronas/fisiología , Transmisión Sináptica , Potenciales de Acción/efectos de la radiación , Animales , Células Cultivadas , Corteza Cerebral/citología , Channelrhodopsins , Técnicas de Cocultivo , Halorrodopsinas/metabolismo , Ratones , Neuronas/efectos de la radiación , Optogenética , Técnicas de Placa-ClampRESUMEN
Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by a polyQ expansion (>36 glutamine repeats) in Huntingtin (Htt) protein. It is believed that dysfunction of corticostriatal system is one of the main pathological events. Special attention is paid to synaptic dysfunction of transmission between cortical and striatal neurons. This review focuses on modern concepts of molecular and cellular mechanisms of HD pathology and especially on alterations in corticostriatal connectivity. Calcium hypothesis of HD and new pharmacological targets are described.