Faculty Bibliography

There is evidence that BDNF influences the birth of granule cells in the dentate gyrus, which is one of the few areas of the brain that demonstrates neurogenesis throughout life. However, studies to date have not examined this issue directly. To do so, we compared the effects of BDNF, phosphate-buffered saline (PBS), or bovine serum albumin (BSA) on neurogenesis after infusion into the hippocampus of the normal adult rat, using osmotic pumps that were implanted unilaterally in the dorsal hilus. BDNF, PBS, and BSA were infused for 2 weeks. The mitotic marker bromodeoxyuridine (BrdU) was administered twice daily during the 2-week infusion period. At least 1 month after infusion ended, brains were processed immunocytochemically using antibodies to BrdU, a neuronal nuclear protein (NeuN), or calbindin D28K (CaBP), which labels mature granule cells. Stereology was used to quantify BrdU-labeled cells in the dorsal hippocampus that were double-labeled with NeuN or CaBP. There was a statistically significant increase in BrdU(+)/NeuN(+) double-labeled cells in the granule cell layer after BDNF infusion relative to controls. The values for BrdU(+)/NeuN(+) cells were similar to BrdU(+)/CaBP(+) cells, indicating that most new neurons were likely to be granule cells. In addition, BrdU(+)/NeuN(+)-labeled cells developed in the hilar region after BDNF infusion, which have previously only been identified after severe continuous seizures (status epilepticus) and associated pathological changes. Remarkably, neurogenesis was also increased contralaterally, but BDNF did not appear to spread to the opposite hemisphere. Thus, infusion of BDNF to a local area can have widespread effects on hippocampal neurogenesis. The results demonstrate that BDNF administration to the dentate gyrus leads to increased neurogenesis of granule cells. They also show that ectopic granule cells develop after BDNF infusion, which suggests that ectopic migration is not necessarily confined to pathological conditions. These results are discussed in light of the evidence that BDNF increases neuronal activity in hippocampus. Thus, the mechanisms underlying neurogenesis following BDNF infusion could be due to altered activity as well as direct effects of BDNF itself, and this is relevant to studies of other growth factors because many of them have effects on neuronal excitability that are often not considered

The principal ovarian estrogen, estradiol, and brain-derived neurotrophic factor (BDNF) have widespread effects on the CNS that have usually been studied independently. This article examines the similarities in the effects of estradiol and BDNF in the hippocampus, in light of the evidence that estradiol can induce BDNF expression, and recent data suggesting that structural and electrophysiological effects of estradiol in the hippocampus might be mediated by BDNF. The possible role of BDNF as a signaling molecule downstream of estrogen in the hippocampus has implications for our understanding of several cellular and behavioral hippocampal functions, including dendritic and synaptic plasticity, learning and cognitive behavior. Furthermore, disruption of the relationship between estrogen and BDNF could contribute to neurological and psychiatric disorders that have been associated with the hippocampus, such as Alzheimer's disease, depression and epilepsy

Since the purification of BDNF in 1982, a great deal of evidence has mounted for its central roles in brain development, physiology, and pathology. Aside from its importance in neural development and cell survival, BDNF appears essential to molecular mechanisms of synaptic plasticity. Basic activity-related changes in the central nervous system are thought to depend on BDNF modification of synaptic transmission, especially in the hippocampus and neocortex. Pathologic levels of BDNF-dependent synaptic plasticity may contribute to conditions such as epilepsy and chronic pain sensitization, whereas application of the trophic properties of BDNF may lead to novel therapeutic options in neurodegenerative diseases and perhaps even in neuropsychiatric disorders

Vascular endothelial growth factor (VEGF) is a vascular growth factor which induces angiogenesis (the development of new blood vessels), vascular permeability, and inflammation. In brain, receptors for VEGF have been localized to vascular endothelium, neurons, and glia. VEGF is upregulated after hypoxic injury to the brain, which can occur during cerebral ischemia or high-altitude edema, and has been implicated in the blood-brain barrier breakdown associated with these conditions. Given its recently-described role as an inflammatory mediator, VEGF could also contribute to the inflammatory responses observed in cerebral ischemia. After seizures, blood-brain barrier breakdown and inflammation is also observed in brain, albeit on a lower scale than that observed after stroke. Recent evidence has suggested a role for inflammation in seizure disorders. We have described striking increases in VEGF protein in both neurons and glia after pilocarpine-induced status epilepticus in the brain. Increases in VEGF could contribute to the blood-brain barrier breakdown and inflammation observed after seizures. However, VEGF has also been shown to be neuroprotective across several experimental paradigms, and hence could potentially protect vulnerable cells from damage associated with seizures. Therefore, the role of VEGF after seizures could be either protective or destructive. Although only further research will determine the exact nature of VEGF's role after seizures, preliminary data indicate that VEGF plays a protective role after seizures

The neurobiological doctrine governing the concept of neurogenesis has undergone a revolution in the past few years. What was once considered dubious is now well accepted: new neurons are born in the adult brain. Science fiction is quickly becoming a reality as scientists discover ways to convert skin, bone, or blood cells into neurons. In the epilepsy arena, widespread interest has developed because of the evidence that neurogenesis increases after seizures, trauma, and other insults or injuries that alter seizure susceptibility. This review discusses some of the initial studies in this field, and their often surprising functional implications. The emphasis will be on the granule cells of hippocampus, because they are perhaps more relevant to epilepsy than other areas in which neurogenesis occurs throughout life, the olfactory bulb and subventricular zone. In particular, the following questions will be addressed: 1. Do granule cells that are born in the adult brain become functional, and what are the limits of their function? Do they behave homogeneously? Results from our own laboratory have focused on cells that become established outside the normal boundaries of the granule cell layer, forming a group of 'ectopic' granule cells in the hilar region. 2. Is increased neurogenesis beneficial, or might it actually exacerbate seizures? Evidence is presented that supports the hypothesis that new granule cells may not necessarily act to ameliorate seizures, and might even contribute to them. Furthermore, cognitive deficits following seizures might in part be due to new circuits that develop between new cells and the host brain. 3. How do the new cells interact with the host brain? Several changes occur in the dentate gyrus after seizures, and increased neurogenesis is only one of many. What is the interdependence of this multitude of changes, if any? 4. Is neurogenesis increased after seizures in man? Research suggests that the data from human epileptics are actually inconsistent with the studies in animal models of epilepsy, because there is little evidence of increased neurogenesis in epileptic tissue resected from intractable epileptics. Yet neurogenesis has been shown to occur in humans throughout adult life. What might be the reasons for these seemingly disparate results?

To test the hypothesis that induction of BDNF may contribute to changes in hippocampal excitability occurring during the female reproductive cycle, we examined the distribution of BDNF immunoreactivity and changes in CA1 and CA3 electrophysiology across the estrous cycle in rats. Hippocampal BDNF immunoreactivity increased on the day of proestrus as well as on the following morning (estrus), relative to metestrus or ovariectomized animals. Changes in immunoreactivity were clearest in mossy fiber axons of dentate gyrus granule cells, which contain the highest concentration of BDNF. Increased immunoreactivity was also apparent in the neuropil-containing dendrites of CA1 and CA3 neurons. Electrophysiological recordings in hippocampal slices showed robust cycle-dependent differences. Evoked responses of CA1 neurons to Schaffer collateral stimulation changed over the cycle, with larger maximum responses at both proestrus and estrus relative to metestrus. In area CA3, repetitive hilar stimuli frequently evoked multiple population spikes at proestrus and estrus but only rarely at other cycle stages, and never in slices of ovariectomized rats. Hyperexcitability in area CA3 at proestrus was blocked by exposure to the high-affinity neurotrophin receptor antagonist K252a, or an antagonist of the alpha7 nicotinic cholinergic receptor, whereas it was induced at metestrus by the addition of BDNF to hippocampal slices. These studies suggest that hippocampal BDNF levels change across the estrous cycle, accompanied by neurophysiological responses that resemble the effects of BDNF treatment. An estrogen-induced interaction of BDNF and alpha7 nicotinic receptors on mossy fibers seems responsible for estrous cycle changes in area CA3. Periovulatory changes in hippocampal function may, thus, involve estrogen-induced increases in BDNF expression