Abstract
Adult neurogenesis in the hippocampus is a remarkable phenomenon involved in various aspects of learning and memory as well as disease pathophysiology. Brain-derived neurotrophic factor (BDNF) represents a major player in the regulation of this unique form of neuroplasticity, yet the mechanisms underlying its pro-neurogenic actions remain unclear. Here, we examined the effects associated with brief (25 min), unilateral infusion of BDNF in the rat dentate gyrus. Acute BDNF infusion induced long-term potentiation (LTP) of medial perforant path-evoked synaptic transmission and, concomitantly, enhanced hippocampal neurogenesis bilaterally, reflected by increased dentate gyrus BrdU + cell numbers. Importantly, inhibition of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) translation through local, unilateral infusion of anti-sense oligodeoxynucleotides (ArcAS) prior to BDNF infusion blocked both BDNF-LTP induction and the associated pro-neurogenic effects. Notably, basal rates of proliferation and newborn cell survival were unaltered in homozygous Arc/Arg3.1 knockout mice. Taken together these findings link the pro-neurogenic effects of acute BDNF infusion to induction of Arc/Arg3.1-dependent LTP in the adult rodent dentate gyrus.
Highlights
Is required for stable expansion of the actin cytoskeleton at perforant path synapses
BDNF infusion promotes the induction of LTP which lasts for at least 15 hours in anesthetized rats, rapidly activates the extracellular signal regulated protein kinase (ERK)[25,26] and requires transcription of new Arc mRNA and new Arc protein synthesis[17,24]
In the present experiment, BDNF infusion led to a robust increase in the fEPSP slope and population spike amplitude, an effect which was inhibited by Arc/Arg3.1 anti-sense oligodeoxynucleotide (ArcAS) infusion but not ArcASScr (Fig. 2)
Summary
Is required for stable expansion of the actin cytoskeleton at perforant path synapses. Inhibition of Arc/Arg3.1 synthesis with anti-sense oligodeoxynucleotides blocks development of stable LTP17. Prior to BDNF, Arc/Arg3.1 anti-sense oligodeoxynucleotides (ODNs) (“ArcAS”) or scrambled Arc ODN sequence control (“ArcASScr”) were administered locally and unilaterally. We hypothesized that if BDNF-mediated pro-neurogenic actions were mediated by LTP induction, inhibition of Arc/Arg3.1 translation would block these effects. Unilateral infusion of ArcAS blocked bilateral changes in proliferation, indicating that the BDNF-induced proliferative response is a consequence of the unilateral induction of Arc/Arg3.1-dependent BDNF-LTP. We compared basal levels of proliferation between Arc/Arg3.1 knockout and wild-type mice and found no significant differences. Together these data suggest that exogenous BDNF enhances neurogenesis indirectly by a mechanism involving LTP induction in the adult granule cell population. The data do not rule out a role for Arc/Arg3.1 synthesis in progenitor cells in neurogenesis
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