Abstract
Late-phase long term potentiation (L-LTP) is thought to be the cellular basis for long-term memory (LTM). While LTM as well as L-LTP is known to depend on transcription and translation, it is unclear why brain-derived neurotrophic factor (BDNF) could sustain L-LTP when protein synthesis is inhibited. The persistently active protein kinase ζ (PKMζ) is the only molecule implicated in perpetuating L-LTP maintenance. Here, in mouse acute brain slices, we show that inhibition of PKMζ reversed BDNF-dependent form of L-LTP. While BDNF did not alter the steady-state level of PKMζ, BDNF together with the L-LTP inducing theta-burst stimulation (TBS) increased PKMζ level even without protein synthesis. Finally, in the absence of de novo protein synthesis, BDNF maintained TBS-induced PKMζ at a sufficient level. These results suggest that BDNF sustains L-LTP through PKMζ in a protein synthesis-independent manner, revealing an unexpected link between BDNF and PKMζ.
Highlights
LTP in acute hippocampus slices has long been used as a model to study the cellular mechanisms underlying learning and memory
PKMf mediates brain-derived neurotrophic factor (BDNF)-dependent late phase LTP Previous studies indicate that L-LTP can be further divided into the BDNF-dependent form which can be induced by theta burst stimulation (12 theta-burst stimulation (TBS)) or a perfusion of cAMP analogs such as forskolin, and the BDNF-independent form which is triggered by the classic 4 sets of tetanus (46tetani) [20]
L-LTP is known to be dependent on translation, it has been puzzling why BDNF could rescue the L- LTP deficit in the presence of the protein synthesis inhibitor anisomycin [5]
Summary
LTP in acute hippocampus slices has long been used as a model to study the cellular mechanisms underlying learning and memory. The secreted trophic protein BDNF and intracellular signaling molecule PKMf are the two best-studied molecules; both are necessary and sufficient to maintain L-LTP [5,6,7,8,9]. PKMf is a brain-specific, atypical isoform of protein kinase C. It is persistently active, due largely to the lack of regulatory domain and second-messenger-independent [11]. BDNF and PKMf share several common characteristics in regulating hippocampal L-LTP. Inhibition of either BDNF or PKMf abolishes L-LTP [5,15]. The relationships between the two molecules in regulating L-LTP remain unclear
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