Kinases RIPK1 and RIPK3 are involved in the mechanism of axonal and dendrite degeneration in cultured hippocampal neurons exposed to glutamate excitotoxicity

Axons and dendrites are neuronal extensions known as neurites that allow the formation of neuronal networks and neuronal communication. Neurite degeneration induces connectivity loss in the central nervous system (CNS) and precedes neuronal death in several CNS diseases. The axonal degeneration mechanism depends on mitochondrial depolarization, the opening of the mitochondrial permeability transition pore (mPTP) and calcium increase in the axoplasm, but currently a signaling pathway controlling the axonal degeneration mechanism remains unknown. RIPK1 and RIPK3 are two kinases that control a necrotic-like mechanism of programmed cell death known as necroptosis, which have been related to CNS disease. The current work propose that RIPK1 and RIPK3 activation controls the degeneration of axons and dendrites in hippocampal neurons exposed to glutamate excitotoxicity, a common damage mechanism associated to several pathologies of the CNS.

Using cultured rat embryo hippocampal neurons, the effects of RIPK1 inhibition and RIPK3 knock-down over glutamate induced neurite degeneration, neuronal death, and activation of the neurite degeneration mechanism were evaluated. The inhibition of RIPK1 and the knock-down of RIPK3 prevented glutamate-induced neurite degeneration, but were not able to prevent neuronal apoptotic-cell death. RIPK1 inhibition also prevented mitochondrial depolarization, the opening of the mPTP and the sustained increase in neurite citoplasmatic calcium induced by the glutamate treatment.

These data show that RIPK1 and RIPK3 are involved in the axonal and dendrite degeneration of hippocampal neurons damaged by glutamate excitotoxicity and suggest that a necroptotic-like signaling may control the neurite degeneration mechanism in CNS neurons.

• Nombre: Diego Hernández Trejo
• Laboratorio: Neurobiología
• Mención: Ciencias Fisiológicas
• Director Tesis: Felipe Court