Vías de señalización mTOR y AKT en epilepsia / Signaling pathways mTOR and AKT in epilepsy

Introducción. La vía de señalización AKT/mTOR es un eje central en la regulación celular, especialmente en las enfermedades neurológicas. En la epilepsia, se ha evidenciado su alteración dentro de su proceso fisiopatológico. Sin embargo, aún no se han descrito todos los mecanismos de estas rutas de señalización, las cuales podrían abrir la puerta hacia nuevas investigaciones y estrategias terapéuticas, que finalmente permitan desarrollar tratamientos efectivos en enfermedades neurológicas como la epilepsia. Objetivo. Revisar las asociaciones existentes entre las rutas de señalización intracelular de mTOR y AKT en la fisiopatología de la epilepsia. Desarrollo. La epilepsia es una enfermedad neurológica con un alto impacto epidemiológico en el mundo, por lo cual es de sumo interés la investigación de los componentes fisiopatológicos que puedan generar nuevos tratamientos farmacológicos. En esta búsqueda se han involucrado diferentes rutas de señalización intracelular en neuronas, como determinantes epileptógenos. Los avances en esta materia han permitido incluso la implementación de nuevas estrategias terapéuticas exitosas y que abren el camino hacia nuevas investigaciones. Conclusiones. Mejorar los conocimientos respecto al papel fisiopatológico de la vía de señalización mTOR/AKT en la epilepsia permite plantear nuevas investigaciones que ofrezcan nuevas alternativas terapéuticas para el tratamiento de la enfermedad. El uso de inhibidores de mTOR ha surgido en los últimos años como una alternativa eficaz en el tratamiento de algunos tipos de epilepsias, pero es evidente la necesidad de seguir en la búsqueda de nuevas terapias farmacológicas involucradas en estas vías de señalización (AU)

Introduction. The signaling pathway AKT/mTOR is a central axis in regulating cellular processes, particularly in neurological diseases. In the case of epilepsy, it has been observed alteration in the pathophysiological process of the same. However, they have not described all the mechanisms of these signaling pathways that could open the opportunity to new research and therapeutic strategies. Aim. To review existing partnerships between intracellular signaling pathways AKT and mTOR in the pathophysiology of epilepsy. Development. Epilepsy is a disease with a high epidemiological impact globally, so it is widely investigated regarding the pathophysiological components thereof. In that search they have been involved different intracellular signaling pathways in neurons, as determinants epileptogenic. Advances in this field have even allowed the successful implementation of new therapeutic strategies and to open the way to new research in the field. Conclusions. Improving knowledge about the pathophysiological role of the signaling pathway mTOR/AKT in epilepsy can raise new investigations regarding therapeutic alternatives. The use of mTOR inhibitors, has emerged in recent years as effective in treating this disease entity alternative however is clear the necessity of continue the research for new drug therapies (AU)

Functional upregulation of Ca(2+)-activated K(+) channels in the development of substantia nigra dopamine neurons.

Many connections in the basal ganglia are made around birth when animals are exposed to a host of new affective, cognitive, and sensori-motor stimuli. It is thought that dopamine modulates cortico-striatal synapses that result in the strengthening of those connections that lead to desired outcomes. We propose that there must be a time before which stimuli cannot be processed into functional connections, otherwise it would imply an effective link between stimulus, response, and reward in uterus. Consistent with these ideas, we present evidence that early in development dopamine neurons are electrically immature and do not produce high-frequency firing in response to salient stimuli. We ask first, what makes dopamine neurons immature? and second, what are the implications of this immaturity for the basal ganglia? As an answer to the first question, we find that at birth the outward current is small (3nS-V), insensitive to Ca(2+), TEA, BK, and SK blockers. Rapidly after birth, the outward current increases to 15nS-V and becomes sensitive to Ca(2+), TEA, BK, and SK blockers. We make a detailed analysis of the kinetics of the components of the outward currents and produce a model for BK and SK channels that we use to reproduce the outward current, and to infer the geometrical arrangement of BK and Ca(2+) channels in clusters. In the first cluster, T-type Ca(2+) and BK channels are coupled within distances of ~20 nm (200 Å). The second cluster consists of L-type Ca(2+) and BK channels that are spread over distances of at least 60 nm. As for the second question, we propose that early in development, the mechanism of action selection is in a "locked-in" state that would prevent dopamine neurons from reinforcing cortico-striatal synapses that do not have a functional experiential-based value.