Modulation of Synaptic Function by Neurotrophic Factors in the Adult Hippocampus

The neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), are a group of signaling factors that are crucial for neuronal survival and differentiation during development. Previous studies have shown that the hippocampus is a prominent site of expression of the neurotrophins and their Trk receptors in the adult brain. Interestingly, the expression of BDNF, NT-3, and their receptors can be regulated by a variety of neuronal activity, which suggests that the neurotrophins may also participate in adult synaptic plasticity. The possibility that the neurotrophins directly modulate synaptic strength in the mature brain was investigated at the Schaffer collateral-CAI synapses in the adult rat hippocampus. Transient application of BDNF or NT-3 but not NGF produced a dramatic and sustained (3 to 4 hours) enhancement of synaptic transmission. Both electrophysiological and immunocytochemical evidence indicated that the penetration and the resulting synaptic potentiation by neurotrophins are influenced by the perfusion rate at which the neurotrophin is applied to hippocampal synapses. The potentiating effects ofBDNF and NT-3 could be completely blocked by inhibiting the function of Trk receptors using either a pharmacological inhibitor of tyrosine kinases or a function-blocking Trk antibody. In addition, blockade ofL-type calcium channels or intracellular calcium stores significantly reduced the potentiation induced by either neurotrophin. These data suggest that both the activation of Trk receptors and the subsequent increase in intracellular calcium concentration are essential for the initiation of neurotrophin-induced synaptic enhancement. The neurotrophin-induced plasticity exhibits an immediate requirement for protein synthesis, which is not somatic in origin. The neurotrophins still produced synaptic potentiation at synapses isolated from their cell bodies; this plasticity displayed a dependence on protein synthesis, raising the possibility that these factors may stimulate local protein synthesis within dendrites and promote site-specific modification of synaptic function. Finally, I report that the neurotrophins play a functional role in certain forms of hippocampal long-term potentiation (LTP). The maintenance of LTP induced by thetaburst or pairing, but not strong tetanic stimulation, relied on intact neurotrophin signaling. In long-term LTP, the neurotrophins were primarily involved in maintaining the late phases of synaptic enhancement, without significantly affecting an early phase of potentiation. Thus, during adult plasticity, synaptic activity-induced increases in neurotrophin synthesis and release contribute to the late phase of LTP and may eventually lead to structural changes at the synapse.