Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders.

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Role of the Basal Forebrain Cholinergic Projection in Somatosensory Cortical Plasticity

Journal of Neurophysiology ◽

10.1152/jn.1998.79.6.3216 ◽

1998 ◽

Vol 79 (6) ◽

pp. 3216-3228 ◽

Cited By ~ 65

Author(s):

Robert N. S. Sachdev ◽

Shao-Ming Lu ◽

Ron G. Wiley ◽

Ford F. Ebner

Keyword(s):

Synaptic Plasticity ◽

Basal Forebrain ◽

Cortical Plasticity ◽

Cortical Cell ◽

Growth Factor Receptor ◽

Nucleus Basalis ◽

Adult Rats ◽

Cholinergic Basal Forebrain ◽

Cholinergic Projection

Sachdev, Robert N. S., Shao-Ming Lu, Ron G. Wiley, and Ford F. Ebner. Role of the basal forebrain cholinergic projection in somatosensory cortical plasticity. J. Neurophysiol. 79: 3216–3228, 1998. Trimming all but two whiskers in adult rats produces a predictable change in cortical cell-evoked responses characterized by increased responsiveness to the two intact whiskers and decreased responsiveness to the trimmed whiskers. This type of synaptic plasticity in rat somatic sensory cortex, called “whisker pairing plasticity,” first appears in cells above and below the layer IV barrels. These are also the cortical layers that receive the densest cholinergic inputs from the nucleus basalis. The present study assesses whether the cholinergic inputs to cortex have a role in regulating whisker pairing plasticity. To do this, cholinergic basal forebrain fibers were eliminated using an immunotoxin specific for these fibers. A monoclonal antibody to the low-affinity nerve growth factor receptor 192 IgG, conjugated to the cytotoxin saporin, was injected into cortex to eliminate cholinergic fibers in the barrel field. The immunotoxin reduces acetylcholine esterase (AChE)-positive fibers in S1 cortex by >90% by 3 wk after injection. Sham-depleted animals in which either saporin alone or saporin unconjugated to 192 IgG is injected into the cortex produces no decrease in AChE-positive fibers in cortex. Sham-depleted animals show the expected plasticity in barrel column neurons. In contrast, no plasticity develops in the ACh-depleted, 7-day whisker-paired animals. These results support the conclusion that the basal forebrain cholinergic projection to cortex is an important facilitator of synaptic plasticity in mature cortex.

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Estradiol Modulation of Neurotrophin Receptor Expression in Female Mouse Basal Forebrain Cholinergic Neurons In Vivo

Endocrinology ◽

10.1210/en.2014-1669 ◽

2014 ◽

Vol 156 (2) ◽

pp. 613-626 ◽

Cited By ~ 17

Author(s):

Michael R. Milne ◽

Christopher A. Haug ◽

István M. Ábrahám ◽

Andrea Kwakowsky

Keyword(s):

Estrogen Receptor ◽

Choline Acetyltransferase ◽

Basal Forebrain ◽

Neuroprotective Effect ◽

Cholinergic Neurons ◽

Receptor Expression ◽

Nucleus Basalis ◽

Neurotrophin Receptor ◽

Ovariectomized Mice ◽

Basal Forebrain Cholinergic Neurons

The neuroprotective effect of estradiol (E2) on basal forebrain cholinergic neurons (BFCNs) has been suggested to occur as a result of E2 modulation of the neurotrophin system on these neurons. The present study provides a comprehensive examination of the relationship between E2 and neurotrophin signaling on BFCNs by investigating the effect of E2 deficiency on the expression levels of neurotrophin receptors (NRs), TrkA, TrkB, and p75 on BFCNs. The number of TrkA receptor-expressing choline acetyltransferase-positive neurons was significantly reduced in the medial septum (MS) in the absence of E2. A significant reduction in TrkB-expressing choline acetyltransferase-positive cells was also observed in ovariectomized mice in the MS and nucleus basalis magnocellularis (NBM). p75 receptor expression was reduced in the NBM and striatum but not in the MS. We also showed that estrogen receptor (ER)-α was expressed by a small percentage of TrkA- and TrkB-positive neurons in the MS (12%) and NBM (19%) and by a high percentage of TrkB-positive neurons in the striatum (69%). Similarly, ERα was expressed at low levels by p75 neurons in the MS (6%) and NBM (9%) but was not expressed on striatal neurons. Finally, ERα knockout using neuron-specific estrogen receptor-α knockout transgenic mice abolished all E2-mediated changes in the NR expression on BFCNs. These results indicate that E2 differentially regulates NR expression on BFCNs, with effects depending on the NR type and neuroanatomical location, and also provide some evidence that alterations in the NR expression are, at least in part, mediated via ERα.

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