The molecular mechanisms and signalling cascades that trigger the induction of group I
metabotropic glutamate receptor (GI-mGluR)-dependent long-term depression (LTD) have been the
subject of intensive investigation for nearly two decades. The generation of genetically modified animals
has played a crucial role in elucidating the involvement of key molecules regulating the induction and
maintenance of mGluR-LTD. In this review we will discuss the requirement of the newly discovered
MAPKAPK-2 (MK2) and MAPKAPK-3 (MK3) signalling cascade in regulating GI-mGluR-LTD.
Recently, it has been shown that the absence of MK2 impaired the induction of GI-mGluR-dependent
LTD, an effect that is caused by reduced internalization of AMPA receptors (AMPAR). As the MK2 cascade directly
regulates tumour necrosis factor alpha (TNFα) production, this review will examine the evidence that the release of TNFα
acts to regulate glutamate receptor expression and therefore may play a functional role in the impairment of GI-mGluRdependent
LTD and the cognitive deficits observed in MK2/3 double knockout animals. The strong links of increased
TNFα production in both aging and neurodegenerative disease could implicate the action of MK2 in these processes.
Keywords: AMPAR trafficking, cognition, GI-mGluR-LTD, hippocampus, MK2, p38 MAPK, TNFα.
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