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Las mutaciones que causan el autismo síndromico definen un eje de la fisiopatología sináptica
Benjamin D Auerbach1, Emily K Osterweil, Mark F Bear
1Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nature
|November 25, 2011
Resumen
La discapacidad intelectual y el autismo pueden derivarse de una síntesis anormal de proteínas neuronales. Este estudio revela que los déficits sinápticos y cognitivos en trastornos genéticos como el complejo de esclerosis tuberosa y el síndrome de X frágil pueden corregirse mediante la modulación de la síntesis de proteínas dentro de un rango óptimo.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Genética La genética.
- Biología del desarrollo Biología del desarrollo.
Sus antecedentes:
- El complejo de esclerosis tuberosa (TSC) y el síndrome del X frágil (FXS) son trastornos genéticos asociados con discapacidad intelectual y autismo.
- Ambas condiciones implican mutaciones en los genes que regulan la síntesis de proteínas neuronales, lo que lleva a la hipótesis de la síntesis excesiva de proteínas como un mecanismo central.
- Comprender el papel preciso de la síntesis de proteínas en estos trastornos es crucial para desarrollar tratamientos efectivos.
Objetivo del estudio:
- Para investigar el papel de la síntesis de proteínas neuronales en la fisiopatología de TSC y FXS.
- Determinar si los déficits sinápticos y cognitivos en modelos de ratón de TSC y FXS se encuentran en extremos opuestos de un espectro fisiológico relacionado con la síntesis de proteínas.
- Explorar estrategias terapéuticas dirigidas al receptor metabotrópico de glutamato 5 (mGluR5) y las interacciones genéticas entre TSC y FXS.
Principales métodos:
- Se utilizaron ensayos electrofisiológicos y bioquímicos para medir la síntesis de proteínas neuronales en el hipocampo de ratones Tsc2(+/-) y Fmr1(-/y).
- Se empleó la modulación farmacológica de mGluR5 para evaluar su efecto sobre los déficits sinápticos, bioquímicos y cognitivos.
- El análisis genético se realizó en ratones reproductores portadores de las mutaciones Tsc2 y Fmr1.
Principales resultados:
- La disfunción sináptica en ratones Tsc2(+/-) y Fmr1(-/y) se produjo en extremos opuestos de un espectro de síntesis de proteínas.
- Los déficits en ambos mutantes fueron mejorados por direcciones opuestas de modulación de mGluR5.
- Las deficiencias cognitivas y sinápticas se rescataron cuando ambas mutaciones estaban presentes en los mismos ratones.
Conclusiones:
- La plasticidad sináptica y la cognición normales se mantienen dentro de un rango óptimo de síntesis de proteínas mediadas por mGluR5.
- Las desviaciones en la síntesis de proteínas en cualquier dirección pueden conducir a trastornos del comportamiento compartidos observados en TSC y FXS.
- Estos hallazgos sugieren un mecanismo subyacente común para la discapacidad intelectual y el autismo relacionado con la regulación de la síntesis de proteínas.
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