Abstract
The mitogen-activated protein kinase (MAPK) cascade has been shown to play an essential role in regulation of cell proliferation and cell differentiation. Although mammalian MAPKs are most abundantly expressed in postmitotic and terminally differentiated neuronal cells, their function in the central nervous system is still largely undefined. We present evidence here for a role of the MAPK cascade in cerebellar long term depression (LTD), which is a widely studied form of synaptic plasticity in mammalian brain. In cultured Purkinje cells, LTD is known to be induced by iontophoretic application of glutamate and depolarization of Purkinje cells. We found that MAPK was activated in Purkinje cells by treatment of primary cultures of rat embryonic cerebella with glutamate and a depolarization-inducing agent, KCl. Application of PD98059, a specific inhibitor of MAPK kinase (MAPKK/MEK), inhibited both the activation of MAPK and the induction of LTD in Purkinje cells. Furthermore, the induction of LTD was completely blocked by introduction into Purkinje cells of anti-active MAPK antibody, which was found to specifically and potently inhibit the activity of MAPK. These results suggest that postsynaptic activation of the MAPK cascade is essential for the induction of cerebellar LTD.
Highlights
Mitogen-activated protein kinase (MAPK,1 known as ERK) is a serine/threonine protein kinase that is commonly activated by various growth factors and differentiation factors [1,2,3]
Because it has been reported that the expression of cerebellar long term depression (LTD) is mediated postsynaptically [23, 24], we first examined whether mitogen-activated protein kinase (MAPK) in cultured Purkinje cells is activated in response to glutamate treatment plus membrane depolarization
Primary cultures of rat embryonic cerebella were treated with simultaneous stimulation with 10 M glutamate and 50 mM KCl for 4 min, the latter being known to induce membrane depolarization in neuronal cells [18]. In another series of experiments, bath application of glutamate plus KCl induced sustained reduction in the amplitudes of miniature excitatory postsynaptic currents recorded from cultured Purkinje cells, suggesting that bath application of glutamate plus KCl can induce cerebellar LTD.3
Summary
Mitogen-activated protein kinase (MAPK,1 known as ERK) is a serine/threonine protein kinase that is commonly activated by various growth factors and differentiation factors [1,2,3]. We found that MAPK was activated in Purkinje cells by treatment of primary cultures of rat embryonic cerebella with glutamate and a depolarization-inducing agent, KCl. Application of PD98059, a specific inhibitor of MAPK kinase (MAPKK/MEK), inhibited both the activation of MAPK and the induction of LTD in Purkinje cells. Because it has been reported that the expression of cerebellar LTD is mediated postsynaptically [23, 24], we first examined whether MAPK in cultured Purkinje cells is activated in response to glutamate treatment plus membrane depolarization.
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