Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells

Multiple insults to the brain lead to neuronal cell death, thus raising the question to what extent can lost neurons be replenished by adult neurogenesis. Here we focused on the hippocampus and especially the dentate gyrus (DG), a vulnerable brain region and one of the two sites where adult neuronal stem cells (NSCs) reside. While adult hippocampal neurogenesis was extensively studied with regard to its contribution to cognitive enhancement, we focused on their underestimated capability to repair a massively injured, nonfunctional DG. To address this issue, we inflicted substantial DG-specific damage in mice of either sex either by diphtheria toxin-based ablation of >50% of mature DG granule cells (GCs) or by prolonged brain-specific VEGF overexpression culminating in extensive, highly selective loss of DG GCs (thereby also reinforcing the notion of selective DG vulnerability). The neurogenic system promoted effective regeneration by increasing NSCs proliferation/survival rates, restoring a nearly original DG mass, promoting proper rewiring of regenerated neurons to their afferent and efferent partners, and regaining of lost spatial memory. Notably, concomitantly with the natural age-related decline in the levels of neurogenesis, the regenerative capacity of the hippocampus also subsided with age. The study thus revealed an unappreciated regenerative potential of the young DG and suggests hippocampal NSCs as a critical reservoir enabling recovery from catastrophic DG damage.Peer reviewe

Frequency-dependent effects of phenytoin on frog junctional transmission: Presynaptic mechanisms

The action of the antiepileptic drug, phenytoin, on junctional transmission at various frequencies of synaptic activation was studied in frog nerve-muscle preparations. Intracellular recordings were made from muscle end-plates, and extracellular focal and subendothelial recordings were obtained from motor nerve terminals and their parent axons, respectively. When the motor nerve was stimulated at 100–200 Hz, exposure to the drug (0.1–0.3 mM) induced intermittent failures of junctional transmission which appeared faster as the rate of stimulation was increased. At these and at lower stimulation frequencies (30–50 Hz), in which failures of transmission occurred only rarely, phenytoin markedly limited the buildup of end-plate potential amplitude during the period of repetitive nerve stimulation (tetanic potentiation). Several lines of evidence suggest that both drug effects are consequent to a frequency-dependent depression of the action potential at motor axons and terminals, which could lead to an intermittent conduction block at the higher rates of stimulation. The selective action of phenytoin on high frequency synaptic transmission may contribute to the specificity shown by this drug in suppressing epileptic seizures while sparing normal neuronal activity

Suppression by phenytoin of convulsant-induced afterdischarges at presynaptic nerve terminals

The mechanisms underlying the induction of afterdischarges at presynaptic nerve terminal by convulsant aminopyridines and their suppression by the anticonvulsant drug phenytoin were studied at the frog neuromusclar preparation. Addition of aminopyridine to the perfusing solution induced the appearance of afterdischarges in motor nerve fibres following their primary response to a single nerve stimulus. The afterdischarges seemed to originate at or near the nerve terminals and to propagate both antidromically and orthodromically. The latter resulted in repetitive activation of the neuromuscular synapse. Focal recordings of nerve terminal potentials suggested that aminopyridines may induce afterdischarges by slowing spike repolarization and thereby producing a prolonged depolarization of nerve terminals. Phenytoin suppressed the aminopyridine-induced afterdischarges and the resultant repetitive excitation of the postsynaptic muscle fibres. This effect of phenytoin was associated with a depression of the action potential at the motor nerve terminals but not at their parent axons. These results single the presynaptic nerve terminals as preferential sites for convulsant and anti-convulsant actions

Activity-dependent depression of nerve action potential by phenytoin

The action of the anticonvulsant drug phenytoin was investigated on the responsiveness of isolated amphibian and human nerves to repetitive stimulation. At low frequencies of stimulation (0.5–25 Hz) the drug (at a concentration of 0.1 mM) had no notable effect on the compound nerve action potential. By contrast, at higher rates of stimulation (50–300 Hz), it produced a progressive decrease in amplitude and integral of the compound action potential. This effect was positively correlated with the frequency of nerve activation and was markedly enhanced by elevating the extracellular K + concentration. Thus, phenytoin induces a use- and frequency-dependent depression of axon conduction, which may contribute to its preferential suppression of the spread of high-frequency seizure discharge in the brain