Brain-derived neurotrophic factor (BDNF) is an extremely potent, positive modulator of theta burst induced long-term potentiation (LTP) in the adult hippocampus. The present studies tested whether the neurotrophin exerts its effects by facilitating cytoskeletal changes in dendritic spines. BDNF caused no changes in phalloidin labeling of filamentous actin (F-actin) when applied alone to rat hippocampal slices but markedly enhanced the number of densely labeled spines produced by a threshold level of theta burst stimulation. Conversely, the BDNF scavenger TrkB-Fc completely blocked increases in spine F-actin produced by suprathreshold levels of theta stimulation. TrkB-Fc also blocked LTP consolidation when applied 1-2 min, but not 10 min, after theta trains. Additional experiments confirmed that p21 activated kinase and cofilin, two actin-regulatory proteins implicated in spine morphogenesis, are concentrated in spines in mature hippocampus and further showed that both undergo rapid, dose-dependent phosphorylation after infusion of BDNF. These results demonstrate that the influence of BDNF on the actin cytoskeleton is retained into adulthood in which it serves to positively modulate the time-dependent LTP consolidation process.

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.

Restoration of neuronal viability and synaptic plasticity through increased trophic support is widely regarded as a potential therapy for the cognitive declines that characterize aging. Previous studies have shown that in the hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested whether increasing endogenous brain-derived neurotrophic factor (BDNF) could reverse this age-related change. We report here that in middle-aged (8- to 10-mo-old) rats, in vivo treatments with a positive AMPA-type glutamate receptor modulator both increase BDNF protein levels in the cortical telencephalon and restore stabilization of basal dendritic LTP as assessed in acute hippocampal slices 18 h after the last drug treatment. These effects were not attributed to enhanced synaptic transmission or to facilitation of burst responses used to induce LTP. Increasing extracellular levels of BDNF by exogenous application to slices of middle-aged rats was also sufficient to rescue the stabilization of basal dendritic LTP. Finally, otherwise stable LTP in ampakine-treated middle-aged rats can be eliminated by infusion of the extracellular BDNF scavenger TrkB-Fc. Together these results indicate that increases in endogenous BDNF signaling can offset deficits in the postinduction processes that stabilize LTP.

Integrin class adhesion proteins are concentrated at adult brain synapses. Whether synaptic integrins engage kinase signaling cascades has not been determined, but is a question of importance to ideas about integrin involvement in functional synaptic plasticity. Accordingly, synaptoneurosomes from adult rat brain were used to test if matrix ligands activate integrin-associated tyrosine kinases, and if integrin signaling targets include NMDA-class glutamate neurotransmitter receptors. The integrin ligand peptide Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) induced rapid (within 5 min) and robust increases in tyrosine phosphorylation of focal adhesion kinase, prolinerich tyrosine kinase 2 and Src family kinases. Increases were similarly induced by the native ligand fibronectin, blocked with neutralizing antibodies to b1 integrin, and not obtained with control peptides, indicating that kinase activation was integrinmediated. Both GRGDSP and fibronectin caused rapid Src kinase-dependent increases in tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B in synaptoneurosomes and acute hippocampal slices. Tests of the physiological significance of the latter result showed that ligand treatment caused a rapid and b1 integrin-dependent increase in NMDA receptor-mediated synaptic responses. These results provide the first evidence that, in adult brain, synaptic integrins activate local kinase cascades with potent effects on the operation of nearby neurotransmitter receptors implicated in synaptic plasticity.

A life-threatening disability after complete spinal cord injury is urinary dysfunction, which is attributable to lack of regeneration of supraspinal pathways that control the bladder. Although numerous strategies have been proposed that can promote the regrowth of severed axons in the adult CNS, at present, the approaches by which this can be accomplished after complete cord transection are quite limited. In the present study, we modified a classic peripheral nerve grafting technique with the use of chondroitinase to facilitate the regeneration of axons across and beyond an extensive thoracic spinal cord transection lesion in adult rats. The novel combination treatment allows for remarkably lengthy regeneration of certain subtypes of brainstem and propriospinal axons across the injury site and is followed by markedly improved urinary function. Our studies provide evidence that an enhanced nerve grafting strategy represents a potential regenerative treatment after severe spinal cord injury.