Abstract
The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1−/− neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons.
Highlights
The brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and the induction of L-long-term potentiation (LTP) at glutamatergic synapses in several brain regions
Using cultures E17 mouse cortical neurons, we observed that RSK2 and PLD1 are highly expressed during the first week of culture, with expression levels for both proteins being maximal at 6 days in vitro (DIV) (Fig. 1A)
BDNF induced a strong increase in phospho-CREB levels (p-CREB), an effect that was almost completely abolished in Pld1−/− neurons (Fig. 2B), in line with the idea that PLD1 activity contributes to the ERK-CREB signalling pathway
Summary
The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. A number of studies using different conditional gene targeted mouse lines and Cre-loxP-mediated excision of Bdnf have led to the conclusion that in vivo the effects of endogenous BDNF in modulating the structure of neurons seem to be extremely specific, depending on the developmental stage, the brain area, as well as the cell-type. Another level of complexity lies in the multiple downstream signalling cascades, as well as the diametrically opposing effects of the pro- and mature forms which act through distinct receptors, tropomyosin-like kinase B (TrkB) and p75 (neurotrophin receptor, NTR) respectively. Manipulating BDNF pathways represents a viable therapeutic approach for a variety of neurological and psychiatric disorders
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