Actions of Brain-Derived Neurotrophic Factor in Slices from Rats with Spontaneous Seizures and Mossy Fiber Sprouting in the Dentate Gyrus

Abstract

This study examined the acute actions of brain-derived neurotrophic factor (BDNF) in the rat dentate gyrus after seizures, because previous studies have shown that BDNF has acute effects on dentate granule cell synaptic transmission, and other studies have demonstrated that BDNF expression increases in granule cells after seizures.Pilocarpine-treated rats were studied because they not only have seizures and increased BDNF expression in granule cells, but they also have reorganization of granule cell "mossy fiber" axons. This reorganization, referred to as "sprouting," involves collaterals that grow into novel areas, i.e., the inner molecular layer, where granule cell and interneuron dendrites are located. Thus, this animal model allowed us to address the effects of BDNF in the dentate gyrus after seizures, as well as the actions of BDNF on mossy fiber transmission after reorganization.In slices with sprouting, BDNF bath application enhanced responses recorded in the inner molecular layer to mossy fiber stimulation. Spontaneous bursts of granule cells occurred, and these were apparently generated at the site of the sprouted axon plexus. These effects were not accompanied by major changes in perforant path-evoked responses or paired-pulse inhibition, occurred only after prolonged (30-60 min) exposure to BDNF, and were blocked by K252a.The results suggest a preferential action of BDNF at mossy fiber synapses, even after substantial changes in the dentate gyrus network. Moreover, the results suggest that activation of trkB receptors could contribute to the hyperexcitability observed in animals with sprouting. Because human granule cells also express increased BDNF mRNA after seizures, and sprouting can occur in temporal lobe epileptics, the results may have implications for understanding temporal lobe epilepsy.Key words: neurotrophin; growth factor; hippocampus; epilepsy; glutamate; tyrosine kinase BDNF is widely recognized as a neurotrophin with an important role in normal development that has both trophic and protective effects (Hofer and Barde, 1988;Alderson et al., 1990;Knüsel et al., 1991;Spina et al., 1992;Yan et al., 1992;Lindholm et al., 1993;Morse et al., 1993;Beck et al., 1994;Cheng and Mattson et al., 1994;Ghosh et al., 1994;Kokaia et al., 1994;Acheson et al., 1995;McAllister et al., 1995;L owenstein and Arsenault, 1996). More recently it has become clear that BDN F also has acute, neuromodulatory effects on synaptic transmission. L ohof et al. (1993) first demonstrated that exposure of neuromuscular cultures to BDNF led to increased EPSC s, and this was followed by reports of related effects in other systems (Le␤man et al

Structural and functional asymmetry in the normal and epileptic rat dentate gyrus

“…All glassware and pipette tips were rinsed in 0.005% bovine albumin before use of BDNF. Previous studies in our laboratory showed that bovine albumin alone did not have detectable effects on hippocampal physiology in either normal or epileptic rats (Scharfman, 1997;Croll et al, 1999;Scharfman et al, 1999). …”

“…Not only do they contain glutamate, but they also contain BDNF, NPY, and other substances. Although BDNF appears to enhance mossy fiber transmission (Scharfman, 1997;Scharfman et al, 1999), NPY has been shown to have primarily inhibitory effects on synaptic transmission (Vezzani et al, 1999b; but see also Gariboldi et al, 1998).…”

“…Not only do they contain glutamate, but they also contain BDNF, NPY, and other substances. Although BDNF appears to enhance mossy fiber transmission (Scharfman, 1997;Scharfman et al, 1999), NPY has been shown to have primarily inhibitory effects on synaptic transmission (Vezzani et al, 1999b; but see also Gariboldi et al, 1998).Other factors, such as the distribution of inhibitory neurons or various afferents to the dentate gyrus, also could influence excitability, independent of mossy fiber sprouting. Thus, the relative paucity of NPY-immunoreactive inhibitory neurons close to the infrapyramidal blade and the relatively weak axonal projection of calretinin-immunoreactive fibers to the infrapyramidal blade could contribute to greater infrapyramidal excitability.…”

Changes in neuropeptide Y protein expression following photothrombotic brain infarction and epileptogenesis

“…NPY expression was found markedly increased in hilar GABAergic interneurons, granule cells and sprouted mossy fibers (Bellmann et al, 1991;Chafetz et al, 1995;Lurton and Cavalheiro, 1997;Scharfman et al, 1999Scharfman et al, , 2002Sperk et al, 1992;Takahashi et al, 2000;Vezzani et al, 1996). NPY in the dentate gyrus can influence synaptic transmission and neurogenesis, demonstrates remarkable plasticity after seizures (Scharfman and Gray, 2006), and may have an anticonvulsive action (Furtinger et al, 2001;Klapstein and Colmers, 1997;Vezzani et al, 1999).…”

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

“…BDNF may promote it, NPY may reduce it. Indeed, BDNF does appear to facilitate seizure-like activity due to mossy fiber actions in animal models of epilepsy [149], and in similar epileptic rats NPY is tonically released and inhibits mossy fiber transmission in rats with chronic seizures [150]. Thus, the cascade of estrogen-BDNF-NPY may regulate seizures much more than previously considered.…”