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Biomedical subjects

B Kirschenbaum

Publications and source records attributed to B Kirschenbaum.

12 recordsLinked to original sources
PubMed1999

Adult subventricular zone neuronal precursors continue to proliferate and migrate in the absence of the olfactory bulb.

Neurons continue to be born in the subventricular zone (SVZ) of the lateral ventricles of adult mice. These cells migrate as a network of chains through the SVZ and the rostral migratory stream (RMS) into the olfactory bulb (OB), where they differentiate into mature neurons. The OB is the only known target for these neuronal precursors. Here, we show that, after elimination of the OB, the SVZ and RMS persist and become dramatically larger. The proportion of dividing [bromodeoxyuridine (BrdU)-labeled] or dying (pyknotic or terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeled) cells in the RMS was not significantly affected at 3 d or 3 weeks after bulbectomy (OBX). However, by 3 months after OBX, the percentage of BrdU-labeled cells in the RMS decreased by half and that of dying cells doubled. Surprisingly, the rostral migration of precursors continued along the RMS after OBX. This was demonstrated by focal microinjections of BrdU and grafts of SVZ cells carrying LacZ under the control of a neuron-specific promoter gene. Results indicate that the OB is not essential for proliferation and the directional migration of SVZ precursors.

Animals↗
PubMed1997

Neuronal precursors of the adult rat subependymal zone persist into senescence, with no decline in spatial extent or response to BDNF.

The adult mammalian brain continues to harbor ependymal/subependymal zone (SZ) precursor cells, which can give rise to neurons in vitro. In adult rats, explants of the rostral 6-7 mm of the SZ give rise to neurons in vitro, and over this entire expanse, neuronal survival is supported specifically by brain-derived neurotrophic factor (BDNF). We asked whether either the (a) spatial distribution, (b) abundance, or (c) BDNF responsiveness of the neuronal precursor population was affected by age. Explants of three rostrocaudally defined regions were taken from both young and old rats (3 and 20 months old, respectively), and cultured in 2% fetal bovine serum-containing media with or without added BDNF (20 ng/ml). The extent of neuronal production by these explants varied only minimally with their level of derivation, such that substantial outgrowth was observed at each level tested. Neuronal outgrowth was marginally higher and more rapid in achieving its maximal extent in the 3-month-old rats compared with their aged counterparts, but neuronal outgrowth was robust at each age tested. The duration of survival of SZ-derived neurons did not differ between the young and old rats. At both ages, BDNF supported the survival of these new adult neurons. The extent of BDNF's influence was independent of both the age of the donor rat and the rostrocaudal level at which the parent SZ explant was taken. Thus, the neuronal precursors of the rat brain persist into senescence; the size of the precursor pool attenuates minimally with age, and its spatial extent remains constant. The neurons generated from these precursors can respond to BDNF throughout life.

Aging↗
PubMed1995

Brain-derived neurotrophic factor promotes the survival of neurons arising from the adult rat forebrain subependymal zone.

Neuronal precursor cells persist in the adult forebrain ependymal/subependymal zone (SZ) and have been found to produce neurons in cultures derived from birds, rodents, and humans. We postulated that the survival of neurons generated from these cells might be constrained in adulthood by the local absence of trophic support. To test this hypothesis, we established explant cultures of adult rat forebrain SZ and assessed the effect of defined neurotrophins on the survival of new neurons arising from these explants. We found that microtubule-associated protein 2+ neurons arose from explants derived from a wide area of the SZ, spanning the rostral 6 mm of the ventricular system. In cultures exposed to brain-derived neurotrophic factor (BDNF), > 35% of new neurons survived at 22 days in vitro (DIV), and > 25% survived at 42 DIV, concurrent with the virtually complete loss of neurons in unsupplemented controls. The surviving cells expressed trkB, the high-affinity receptor for BDNF. In contrast, neither nerve growth factor nor neurotrophic factor 3 enhanced neuronal survival. Thus, BDNF supports the survival of neurons produced by the adult rat forebrain and may act as a permissive factor for neuronal recruitment in adulthood.

Analysis of Variance↗
PubMed1994

N-cadherin and Ng-CAM/8D9 are involved serially in the migration of newly generated neurons into the adult songbird brain.

In the adult avian forebrain, neurons continue to be produced in the subependymal zone (SZ), from which they migrate upon radial fibers. To identify ligands regulating this process, we studied N-cadherin and Ng-CAM/8D9 expression in HVC, a neurogenic region of the canary neostriatum. N-cadherin was relatively restricted to the SZ and was expressed by dividing, [3H]thymidine-labeled precursor cells. However, cellular N-cadherin was down-regulated prior to neuronal migration from the SZ. Addition of anti-N-cadherin Fab hastened neuronal migration from adult SZ explants, without influencing neuronal number. Unlike N-cadherin, Ng-CAM/8D9 was expressed by migrating neurons. Anti-8D9 Fab inhibited neuronal migration upon cultured ependymoglia, which did not express Ng-CAM/8D9. Thus, the departure of new neurons from the adult SZ may require their suppression of N-cadherin, whereas their subsequent migration and survival may depend upon neuronal expression of Ng-CAM/8D9 and its interaction with a heterophilic radial cell receptor.

Animals↗
PubMed1990

Posthoc phosphorylation of proteins derived from ischemic rat hippocampus, striatum and neocortex.

Disruption of the brain's protein phosphorylation system by ischemia may cause irreversible metabolic and structural alterations leading eventually to cell death. To examine the effect of ischemia on the phosphorylation state of brain proteins, tissue homogenates derived from the hippocampus, striatum and neocortex of normal rats and rats subjected to severe forebrain ischemia were phosphorylated with [gamma-32P]ATP. The phosphorylated proteins were separated by two-dimensional polyacrylamide gel electrophoresis and changes were assessed by autoradiography. Cerebral ischemia caused marked alterations of the phosphorylation state of many brain proteins; phosphorylation of some proteins was increased while phosphorylation of others was decreased. Despite differences in the sensitivity of the hippocampus, striatum and neocortex to ischemic injury the direction and approximate magnitude of protein phosphorylation changes caused by ischemia were similar in all three regions. Since the pattern of protein phosphorylation in the ischemia-vulnerable hippocampus was identical to that in the ischemia-resistant paramedian neocortex we conclude that abnormalities of protein phosphorylation may be necessary for ischemic injury to neurons but none are sufficient to explain the selective vulnerability of certain brain regions to ischemic damage.

Animals↗
PubMed1987

Nerve growth factor increases the number of functional Na channels and induces TTX-resistant Na channels in PC12 pheochromocytoma cells.

The PC12 clone is a line of rat pheochromocytoma cells that undergoes neuronal differentiation in the presence of NGF protein. In the absence of NGF, PC12 cells are electrically inexcitable, while after several weeks of NGF treatment they develope Na+ action potentials. Past estimates made by measuring binding of 3H-saxitoxin (STX) indicate that NGF treatment brings about a large increase in Na channel density that is of sufficient magnitude to account for the induction of excitability. We have now used 22Na uptake to measure the Na permeability of PC12 cells before and after long-term NGF treatment. Treatment with NGF does not change the resting Na+ permeability. The alkaloid toxins veratridine and batrachotoxin (BTX) and scorpion toxin were used to activate Na channels. Such studies demonstrate that these toxins induce TTX-sensitive Na uptake in both NGF-treated and untreated cells and reveal differences in functional Na channel numbers per cell and per unit of membrane area that are similar to those found in the STX binding studies. On the other hand, affinities for drugs that activate these channels are not affected by NGF treatment. We also find that NGF-treated PC12 cells contain a population of Na channels with low affinity for TTX. These channels account for 5-20% of total BTX or veratridine-stimulated flux. Thus, NGF has 2 effects regarding the Na channels of PC12 cells: it increases the number of functional Na channels that otherwise behave similarly to those present before NGF treatment, and it induces the presence of TTX-resistant Na channels. These findings indicate that the PC12 model system may serve to study the developmental regulation of Na channel expression and properties.

Animals↗
PubMed1982

Nerve growth factor-induced increase in saxitoxin binding to rat PC12 pheochromocytoma cells.

The PC12 clone is a line of rat pheochromocytoma cells which undergoes neuronal differentiation in the presence of nerve growth factor (NGF) protein. In the absence of NGF, PC12 cells are electrically inexcitable, while after several weeks of NGF treatment, they develop sodium action potentials. The number and density of sodium channels on PC12 cells before and after treatment with NGF were estimated by measuring the binding of [3H]saxitoxin ([3H]STX). The data indicate that [3H]STX binding increases in the NGF-treated cells by 15- to 20-fold per cell, 3- to 10-fold per mg of protein, and an estimated 7-fold per unit area of membrane. The kinetic properties for [3H]STX binding are unchanged, however, by NGF treatment. A Hodgkin-Huxley analysis (Hodgkin, A. L., and A. F. Huxley (1952) J. Physiol. (Lond.) 117: 500-544) suggests that the estimated density of sodium channels in NGF-untreated PC12 cells is sufficient to explain their lack of excitability. On the other hand, the estimated channel density on the NGF-treated cells (30 to 50/micrometers 2) is comparable to that in other excitable systems. Thus, the development of excitability in PC12 cells in response to NGF could be due to the induction of sodium channel synthesis.

Adrenal Gland Neoplasms↗
PubMed1978

Phenylketonuria and scleroderma.

Two mentally retarded siblings, one with severe segmental scleroderma and the other with atrophoderma of Pasini and Pierini, were found at the ages of 6 and 10 years to have phenylketonuria (PKU). The belief that a common pathomechanism exists between morphea and atrophoderma of Pasini and Pierini is supported by the case of the two siblings. Disorders in tryptophan metabolism can occur in both PKU and scleroderma. For a low phenylalanine diet to be effective in PKU, it has to be instituted at an early age. Phenylketonuria should be considered in infants and children with sclerodermatous skin lesions.

Child↗
PubMedDate not supplied

In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain.

It has traditionally been held that the adult brain is incapable of significant self-repair, due in part to its inability to generate new neurons. Nevertheless, rodents and birds have been found to harbor neural precursor cells in adulthood. We asked whether the adult human brain might retain such precursors, by culturing samples of temporal lobe under conditions permissive for neuronal differentiation, while exposed to 3H-thymidine. Adult human temporal lobe cultures, derived from cortex, subcortex, and periventricular subependymal zone (SZ), were incubated for 7-28 d, stained for neuronal and glial antigens, and autoradiographed. Neuron-like cells were found in explant outgrowths and monolayer dissociates of SZ and periventricular white matter, but not cortex; they expressed neuronal antigens including MAP-2, MAP-5, NF, and N-CAM, and were GFAP-. Neurons responded to K+ depolarization with rapid and reversible increases in intracellular Ca2+, with much greater increments than those noted in glia. Although most neurons were not 3H-thymidine labeled, a small number of MAP-2+ and MAP-5+/GFAP- cells did incorporate 3H-thymidine, suggesting neuronal production from precursor mitosis. Rare 3H-thymidine+ neurons were also found in cultures of subventricular white matter; in these, GFAP+ astrocytic mitogenesis was common, while O4+ oligodendrocytes, although the predominant cell type, were largely postmitotic. Thus, the adult human forebrain harbors precursor cells that retain the potential for neuronal production and differentiation in vitro.

Adolescent↗