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Brief exposure to NMDA produces long‐term protection of cerebellar granule cells from apoptosis
Author(s) -
Xifro Xavier,
Malagelada Cristina,
Miñano Alfredo,
RodríguezÁlvarez José
Publication year - 2005
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2005.03935.x
Subject(s) - neuroprotection , nmda receptor , microbiology and biotechnology , excitatory postsynaptic potential , chemistry , kinase , neurotrophic factors , brain derived neurotrophic factor , depolarization , caspase 3 , cerebellum , neuroscience , protein kinase a , biology , apoptosis , programmed cell death , biochemistry , biophysics , inhibitory postsynaptic potential , receptor
Cerebellar granule cells (CGCs) require excitatory inputs to survive during their postnatal migration from the external to the internal granule cell layers. The lack of innervation of mossy fibres induces CGC death by apoptosis. In vitro , CGCs die by apoptosis in the presence of physiological concentrations of KCl (5 m m or K5) but they survive in the presence of depolarizing concentrations of KCl (25 m m or K25) or N ‐methyl‐ d ‐aspartate (NMDA) by a mechanism dependent on calcium influx. The addition of NMDA or K25, for only 24 h, to immature CGCs cultures [2 days in vitro (DIV)] was able to produce a remarkable and long‐term protection until 8 DIV. Moreover, our data show that NMDA and K25‐mediated long‐lasting protection was related to an inhibition of caspase‐3 activity. By using different protein kinase inhibitors, we have shown that the inhibition of caspase‐3 activation by NMDA was dependent on the activation of tyrosine kinases and phosphatidylinositol 3‐kinase (PI3‐kinase). Moreover, an impairment in NMDA‐mediated neuroprotection and caspase‐3 inhibition was observed when the action of brain‐derived neurotrophic factor (BDNF) was blocked. By contrast, K25‐mediated neuroprotection was BDNF‐independent and was mediated by a mitogen‐activated protein kinase‐ and PI3‐kinase‐dependent inhibition of caspase‐3.