BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?

Abstract

It is generally believed that late-phase long-term potentiation (L-LTP) and long-term memory (LTM) require new protein synthesis. Although the full complement of proteins mediating the long-lasting changes in synaptic efficacy have yet to be identified, several lines of evidence point to a crucial role for activity-induced brain-derived neurotrophic factor (BDNF) expression in generating sustained structural and functional changes at hippocampal synapses thought to underlie some forms of LTM. In particular, BDNF is sufficient to induce the transformation of early to late-phase LTP in the presence of protein synthesis inhibitors, and inhibition of BDNF signaling impairs LTM. Despite solid evidence for a critical role of BDNF in L-LTP and LTM, many issues are not resolved. Given that BDNF needs to be processed in Golgi outposts localized at the branch point of one or few dendrites, a conceptually challenging problem is how locally synthesized BDNF in dendrites could ensure synapse-specific modulation of L-LTP. An interesting alternative is that BDNF-TrkB signaling is involved in synaptic tagging, a prominent hypothesis that explains how soma-derived protein could selectively modulate the tetanized (tagged) synapse. Finally, specific roles of BDNF in the acquisition, retention or extinction of LTM remain to be established.

Figures

Figure 1

Activity-dependent secretion of BDNF from presynaptic site (red in A and C) may be necessary for E-LTP, while the long-term maintenance of L-LTP requires sustained supply of BDNF through activity-dependent transcription and translation in the postsynaptic neurons (green in B and C).

Figure 2. Synaptic specificity is lost after locally synthesized proteins at stimulated synapses are processed at Golgi apparatus elsewhere

When synapse A is stimulated with L-LTP inducing protocol, local protein synthesis is initiated. Since no Golgi apparatus is present at synapses, these proteins have to be delivered to Golgi in other places for processing, such as Glogi outpost at dendritic branch point. The newly processed proteins could be shipped back from Golgi to synapse A as well as synapse B on the same dendrite or synapse C on a different dendrite that share the same Golgi outpost. Synapses D and E are less likely to be affected.

Figure 3. Synaptic tagging model

A, Two independent synaptic inputs to the same neuronal population are activated by two stimulating electrodes (S1 and S2). Field EPSPs are monitored by a single recording electrode in the Schaffer collateral region of the CA1. B, When one afferent pathway (S1) is activated by strong tetanus (12 theta burst at 100 Hz), a weak tetanus (4 theta burst at 100 Hz) applied to a second independent pathway (S2) to the same neuron usually induces L-LTP. C, Short-lived synaptic tag can be generated by strong tetanus and weak tetanus, while the PRPs can only be induced by strong tetanus. When one afferent pathway (S1) is activated by strong tetanus, a weak tetanus applied to a second independent pathway (S2) usually induces L-LTP because it creates a tag that captures the PRP induced by the strong tetanus in S1.

Figure 4. Behavioral tagging

A, Schematic diagram of experimental protocol. A rat was placed in a novel environment (open field) for 5 min within 1 hour before training for weak inhibitory avoidance conditioning (IA) and memory was tested at different time after weak IA conditioning. B, Weak inhibitory avoidance conditioning normally results in a STM detectable at 15 minutes, but not 1 or 24 hrs, after training. C, The same weak IA training produces LTM if coupled with novelty exposure. This effect was dependent on protein synthesis, since infusion of anisomycin, a protein synthesis inhibitorimmediately after the pretraining exposure to novelty blocked the formation of LTM, while vehicle control (novel + veh) still produces LTM. When the rat was familiarized with the novel environment before, the open field did not produce LTM when coupled with weak IA (familiar). (Modified from Moncada and Viola, J Neuroscience, 2007)