A Novel Mechanism for the Facilitation of Theta-Induced Long-Term Potentiation by Brain-Derived Neurotrophic Factor

Abstract

Brain-derived neurotrophic factor (BDNF) contributes to the induction of long-term potentiation (LTP) by theta-pattern stimulation, but the specific processes underlying this effect are not known. Experiments described here, using BDNF concentrations that have minor effects on baseline responses, show that the neurotrophin both reduces the threshold for LTP induction and elevates the ceiling on maximal potentiation. The enhanced LTP proved to be as stable and resistant to reversal as that recorded under control conditions. BDNF markedly increased the facilitation of burst responses that occurs within a theta train. This suggests that the neurotrophin acts on long-lasting events that (1) are set in motion by the first burst in a train and (2) regulate the amplitude of subsequent bursts. Whole-cell recordings established that BDNF causes a rapid reduction in the size of the long-lasting afterhyperpolarization (AHP) that follows individual theta bursts. Apamin, an antagonist of type 2 small-conductance Ca 2ϩ -activated potassium (SK2) channels, also reduced hippocampal AHPs and closely reproduced the effects of BDNF on theta-burst responses and LTP. The latter results were replicated with a newly introduced, highly selective inhibitor of SK2 channels. Immunoblot analyses indicated that BDNF increases SK2 serine phosphorylation in hippocampal slices. These findings point to the conclusion that BDNF-driven protein kinase cascades serve to depress the SK2 component, and possibly other constituents, of the AHP. It is likely that this mechanism, acting with other factors, promotes the formation and increases the magnitude of LTP.

Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice

“…33 and 34). F-actin was labeled before electrophysiological recording by using standard protocols (20) …”

“…The selected concentration (2 nM) partially activates actin signaling in adult slices (15) with little, if any, effect on baseline synaptic physiology (20).…”

Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS

“…Thus, both estradiol and BDNF exert some of their actions in CA1 by phosphorylating either NR1 or NR2B, two subunits of the NMDA receptor [14,[47][48][49][50][51][52][53][54][55]. They also have both been shown to influence a specific Ca2+ -dependent potassium current in CA1 pyramidal cells [56][57][58]. The fact that both estradiol and BDNF have these very specific effects argues against independent effects, although it is not inconceivable that they are simply redundant.…”

Synaptic plasticity in early aging

“…Time 0 shows the events that transpire after the arrival of a theta burst (four action potentials in 30 ms) over the glutamatergic input. Initially this causes a pronounced depolarization of the target cell (indicated by red) but this is quickly counterbalanced by activation voltage-and calcium-dependent potassium channels that generate AHPs lasting from tens of milliseconds to seconds (Stocker et al, 1999;Kramár et al, 2004). These AHPs, initiated by the early bursts, tend to reduce the depolarization associated with subsequent bursts.…”

“…After TBS-induced release, BDNF levels remain elevated in the extracellular space for about 10 min (Aicardi et al, 2004). Mature BDNF (mBDNF), at 2 nM concentrations, doubles the amount of LTP produced by a standard theta burst train and greatly reduces the number of bursts needed to produce a significant degree of stable potentiation (Kramár et al, 2004). Equally important, a fusion construct that scavenges endogenous (extracellular) mBDNF completely blocks the formation of stable LTP (Chen et al, 1999).…”