Faculty Bibliography

In addition to its potent effects on vasculature, it has become clear that vascular endothelial growth factor (VEGF) has effects on both neurons and glia, and recent studies suggest that it can be neuroprotective. To determine potential mechanisms underlying this neuroprotection, recombinant human VEGF was bath applied to adult rat hippocampal slices, and both extracellular and intracellular recordings were used to examine intrinsic properties and synaptic responses of hippocampal principal neurons. Initial studies in area CA1 showed that VEGF significantly reduced the amplitude of responses elicited by Schaffer collateral stimulation, without influencing membrane properties. Similar effects occurred in CA3 pyramidal cells and dentate gyrus granule cells when their major glutamatergic afferents were stimulated. Because VEGF expression is increased after seizures, effects of VEGF were also examined in rats with recurrent spontaneous seizures. VEGF reduced spontaneous discharges in slices from these rats but had surprisingly little effect on epileptiform discharges produced by disinhibition of slices from control rats. These results demonstrate a previously unknown effect of VEGF on neuronal activity and also demonstrate a remarkable potency in the epileptic brain. Based on this, we suggest that VEGF or VEGF-related targets could provide useful endpoints to direct novel therapeutic strategies for epilepsy

PURPOSE: The tryptophan metabolite kynurenic acid (KYNA) and its synthetic derivative, 7-chlorokynurenic acid (7-Cl-KYNA), are antagonists of the glycine co-agonist ('glycine(B)') site of the N-methyl-D-aspartate (NMDA)-receptor. Both compounds have neuroprotective and anticonvulsive properties but do not readily penetrate the blood-brain barrier. However, KYNA and 7-Cl-KYNA can be formed in, and released from, astrocytes after the peripheral administration of their transportable precursors kynurenine and 4-chlorokynurenine, respectively. The present study was designed to examine these biosynthetic processes, as well as astrogliosis, in animals with spontaneously recurring seizures. METHODS: The fate and formation of KYNA and 7-Cl-KYNA was studied in vivo (microdialysis) and in vitro (tissue slices) in rats exhibiting chronic seizure activity (pilocarpine model) and in appropriate controls. Neuronal loss and gliosis in these animals were examined immunohistochemically. RESULTS: In vivo microdialysis revealed higher ambient extracellular KYNA levels and enhanced de novo formation of 7-Cl-KYNA in the entorhinal cortex and hippocampus in epileptic rats. Complementary studies in tissue slices showed increased neosynthesis of KYNA and 7-Cl-KYNA in the same two brain areas. Microscopic analysis revealed pronounced astrocytic reactions in entorhinal cortex and hippocampus in epileptic animals. CONCLUSIONS: These results demonstrate that the epileptic brain can synthesize glycine(B) receptor antagonists in situ. Astrogliosis probably accounts for their enhanced production in chronically epileptic rats. These results bode well for the use of 4-chlorokynurenine in the treatment of chronic seizure disorders

Adult dentate neurogenesis is important for certain types of hippocampal-dependent learning and also appears to be important for the maintenance of normal mood and the behavioural effects of antidepressants. Neuropeptide Y (NPY), a peptide neurotransmitter released by interneurons in the dentate gyrus, has important effects on mood, anxiety-related behaviour and learning and memory. We report that adult NPY receptor knock-out mice have significantly reduced cell proliferation and significantly fewer immature doublecortin-positive neurons in the dentate gyrus. We also show that the neuroproliferative effect of NPY is dentate specific, is Y1-receptor mediated and involves extracellular signal-regulated kinase (ERK)1/2 activation. NPY did not exhibit any effect on cell survival in vitro but constitutive loss of the Y1 receptor in vivo resulted in greater survival of newly generated neurons and an unchanged total number of dentate granule cells. These results show that NPY stimulates neuronal precursor proliferation in the dentate gyrus and suggest that NPY-releasing interneurons may modulate dentate neurogenesis

It has been known for some time that brain-derived neurotrophic factor (BDNF) is critical to normal development of the CNS, and more recently, studies also have documented the ability of BDNF to modify adult CNS structure and function. Therefore, it is no surprise that BDNF has been linked to diseases, such as epilepsy, which may involve abnormal cortical development or altered brain structure and function after maturity. This review evaluates the evidence, particularly from recent studies, that BDNF contributes to the development of temporal lobe epilepsy (TLE)

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