Neurotrophic factors are important regulators of neuronal development and survival, yet the functions of neurotrophins in the adult brain are still little understood. Recent evidence suggests that one of the neurotrophins, brain-derived neurotrophic factor (BDNF), plays a critical role in activity-dependent synaptic plasticity. We have examined the effects of local BDNF infusion on synaptic efficacy at medial perforant path granule cell synapses in the dentate gyrus of anesthetized rats.

Infusion of BDNF (2 µg in 2 µl, 25 min) into the dentate gyrus led to a long-term potentiation of synaptic transmission termed BDNF-LTP. BDNF-LTP requires activation of extracellular signal-regulated kinase (ERK), and is coupled to ERK-dependent phosphorylation of CREB and upregulation of the immediate early gene Arc (activity-dependent cytoskeleton-associated protein). Arc mRNA is rapidly induced in postsynaptic granule cells bodies and delivered to granule cell dendrites. Local infusion of MEK inhibitors (PD98059, U0126) or the RNA synthesis inhibitor actinomycin D blocked BDNF-LTP and the associated upregulation of Arc. Defining a rapid time window of activation, these inhibitors had no effect on established BNDF-LTP. Zif268, another early gene required for generation of transcription-dependent LTP, was not induced. The functional role of BDNF-LTP was assessed in occlusion experiments with classical high-frequency stimulation-induced LTP (HFS-LTP). HFS-LTP was induced and BDNF was infused at time points corresponding to early phase (1 h) and late phase (4 h) HFS-LTP. BDNF applied during the early phase led to normal BDNF-LTP, indicating lack of occlusion. In contrast, BDNF had no effects when it was applied during late, protein synthesis-dependent LTP, indicating occlusion. Taken together, the results suggest that BDNF acts as a synaptic consolidation factor, effectively governing the switch from transcription-independent to transcription-dependent LTP. Further work shows that BDNF also modulates translation control processes. α-CaMKII mRNA, which is constitutively expressed in granule cell dendrites in adult rats, is an attractive target for regulation. For example, in isolated synaptodendrosomes, BDNF treatment induces a rapid (3-5 min) increase in CaMKII protein levels paralleled by an increase in CaMKII activity. In awake rats, high-frequency stimulation of the perforant pathway induces rapid delivery of pre-existing CaMKII mRNA to synapses coupled to enhanced expression of CaMKII protein.

In conclusion current evidence from our laboratory suggests that BDNF regulates synaptic consolidation through dual regulation of transcription and translation. We are currently examining the hypothesis that Arc, a dendritic mRNA species, is causally involved in BDNF-induced LTP.