Hippocampal Precursor Cells Research Articles

Prolonged cultivation of hippocampal neural precursor cells shifts their differentiation potential and selects for aneuploid cells

Neural precursor cells (NPCs) are lineage-restricted neural stem cells with limited self-renewal, giving rise to a broad range of neural cell types such as neurons, astrocytes, and oligodendrocytes. Despite this developmental potential, the differentiation capacity of NPCs has been controversially discussed concerning the trespassing lineage boundaries, for instance resulting in hematopoietic competence. Assessing their in vitro plasticity, we isolated nestin+/Sox2+, NPCs from the adult murine hippocampus. In vitro-expanded adult NPCs were able to form neurospheres, self-renew, and differentiate into neuronal, astrocytic, and oligodendrocytic cells. Although NPCs cultivated in early passage efficiently gave rise to neuronal cells in a directed differentiation assay, extensively cultivated NPCs revealed reduced potential for ectodermal differentiation. We further observed successful differentiation of long-term cultured NPCs into osteogenic and adipogenic cell types, suggesting that NPCs underwent a fate switch during culture. NPCs cultivated for more than 12 passages were aneuploid (abnormal chromosome numbers such as 70 chromosomes). Furthermore, they showed growth factor-independent proliferation, a hallmark of tumorigenic transformation. In conclusion, our findings substantiate the lineage restriction of NPCs from adult mammalian hippocampus. Prolonged cultivation results, however, in enhanced differentiation potential, which may be attributed to transformation events leading to aneuploid cells.

FTY720, Sphingosine 1-Phosphate Receptor Modulator, Attenuates Radiation-Induced Neurocognitive Deficits in Young Mice

Cranial irradiation is an effective treatment modality for both primary and metastatic brain tumors, yet it induces cognitive decline in a substantial number of patients. Recent investigations have revealed a link between radiation-induced cognitive dysfunction and the loss of neural stem cells (NSCs) in the hippocampus. Previously, we showed that FTY720, an agent recently approved by the FDA for treatment of multiple sclerosis, provided radioprotection for NSCs but not tumor cells in vitro. We now examined the ability of fingolimod to mitigate neurocognitive deficits, induced by whole brain irradiation (WBI), in a mouse model. Six-week-old C57/Bl/6J mice were randomized to four experimental groups: (1) WBI + FTY720, (2) WBI + drug vehicle control, (3) sham irradiation + FTY720, and (4) sham irradiation + vehicle. There were 12 mice in each group. Following a single dose of radiation, 7 Gy or 0 Gy (sham), FTY720 or vehicle was given to mice via i.p. injections three times a week for six weeks. Spatial memory was tested using Morris water maze studies. The mice were trained to locate a submerged hidden platform in daily sessions for five days; this was followed by a single probe trial with no platform. The average latency time (length of time to find the platform in water) was calculated for each animal in each trial. Additional behavioral studies included open field, elevated plus maze, and cued fear conditioning studies, testing locomotor activity, anxiety, and amygdala-driven cued response respectively. All data were analyzed using STATA statistical software. In irradiated mice (WBI + vehicle), spatial memory deficits were manifested by significantly longer latency times compared to the non-irradiated controls (sham + vehicle), p < 0.05. Administration of FTY720 fully attenuated radiation-induced memory dysfunction: latency times of irradiated mice treated with FTY720 (WBI + FTY720) were not significantly different from those of non-irradiated controls (sham + vehicle). The latency times of non-irradiated mice treated with FTY720 (sham + FTY720) were equal to those of the non-irradiated vehicle controls (sham + vehicle) as well as of the irradiated FTY720-treated group (WBI + FTY720). There were no statistically significant differences between any of the groups in the open field, elevated plus maze, or fear conditioning studies. We found FTY720 to attenuate radiation-induced spatial memory dysfunction in vivo. Combined with our previous data demonstrating the radioprotective effects of FTY720 on hippocampal neural precursor cells but not tumor cells in vitro, these results provide a strong rationale for testing the efficacy of this FDA-approved agent as a neuroprotector in patients undergoing whole brain radiation therapy.

Jiaweisinisan facilitates neurogenesis in the hippocampus after stress damage.

The traditional Chinese medicine Jiaweisinisan has antidepressant effects, and can inhibit hypothalamus-pituitary-adrenal gland axis hyperactivity in stress-induced depression. In this study, rat hippocampal neural precursor cells were cultured in serum-free medium in vitro and a stress damage model was established with 120 μM corticosterone. Cells were treated with 10% (v/v) Jiaweisinisan drug-containing serum and the corticosterone antagonist RU38486. Results of the 3-(4,5-dimethylthiazol-2-yl)-3,5-di-phenytetrazoliumromide assay showed that both Jiaweisinisan drug-containing serum and RU38486 promoted the proliferation of neural precursor cells after corticosterone exposure. Immunofluorescence detection showed that after Jiaweisinisan drug-containing serum and RU38486 treatment, the 5-bromo-2-deoxyuridine/terminal deoxynucleotidyl transferase dUTP nick end labeling ratio in hippocampal neural precursor cells significantly increased, and the apoptotic rates of glial cells reduced, and neuron-like cell differentiation from neural precursor cells significantly increased. Our experimental findings indicate that Jiaweisinisan promotes hippocampal neurogenesis after stress damage.

Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation

Adult hippocampal neurogenesis is modulated by a number of intrinsic and extrinsic factors including local signalling molecules, exercise, aging and inflammation. Inflammation is also a major contributor to several hippocampal-associated disorders. Interleukin-1beta (IL-1β) is the most predominant pro-inflammatory cytokine in the brain, and an increase in its concentration is known to decrease the proliferation of both embryonic and adult hippocampal neural precursor cells (NPCs). Recent research has focused on the role of nuclear receptors as intrinsic regulators of neurogenesis, and it is now established that the orphan nuclear receptor TLX is crucial in maintaining the NPC pool in neurogenic brain regions. To better understand the involvement of TLX in IL-1β-mediated effects on hippocampal NPC proliferation, we examined hippocampal NPC proliferation and TLX expression in response to IL-1β treatment in an adult rat hippocampal neurosphere culture system. We demonstrate that IL-1β reduced the proliferation of hippocampal NPCs and TLX expression in a dose and time-dependent manner and that co-treatment with IL-1β receptor antagonist or IL-1 receptor siRNA prevented these effects. We also report a dose-dependent effect of IL-1β on the composition of cell phenotypes in the culture and on expression of TLX in these cells. This study thus provides evidence of an involvement of TLX in IL-1β-induced changes in adult hippocampal neurogenesis, and offers mechanistic insight into disorders in which neuroinflammation and alterations in neurogenesis are characteristic features.

Chronic exposure to stress hormones alters the subtype of store‐operated channels expressed in H19‐7 hippocampal neuronal cells

Differentiating H19-7 hippocampal precursor cells up-regulate (∼4.3-fold) store-operated channel (SOC) activity; relatively linear current-voltage curves indicate an I(SOC) subtype of SOC. In differentiated H19-7 neurons, the majority of agonist (arginine vasopressin, AVP)-stimulated Ca(2+) entry occurs via SOCs, based on 2-aminoethyldiphenylborinate (2-APB) inhibition data and the observation that transient receptor potential C1 (TRPC1) channel knock down cells show a dramatic reduction of thapsigargin-stimulated store-operated Ca(2+) entry (SOCE) and inhibition of AVP-stimulated Ca(2+) entry. Treatment of H19-7 cells with the rat stress hormone corticosterone during differentiation induces a significant increase in AVP-stimulated Ca(2+) entry, which is virtually eliminated by 2-APB, suggesting a corticosterone-induced increase of SOCE. Corticosterone also enhances AVP-stimulated Mn(2+) entry, confirming an elevated Ca(2+) entry pathway, rather than a decreased Ca(2+) extrusion. When corticosterone addition is delayed until after H19-7 cells have fully differentiated, it still elevates SOCE. In corticosterone-treated H19-7 cells, the knock down of TRPC1 no longer blocks thapsigargin-stimulated Ca(2+) entry suggesting that the subtype of SOCs expressed in H19-7 cells is altered by corticosterone treatment. Electrophysiological studies demonstrate that store-operated currents in corticosterone-treated H19-7 cells exhibit a highly inward rectifying current-voltage curve consistent with an I(CRAC) subtype of SOCs. Consistent with this finding is the observation that corticosterone treatment of H19-7 cells increases the expression of the I(CRAC) channel subunit Orai1. Thus, the subtype of SOCs expressed in H19-7 hippocampal neurons can be altered from I(SOC) to I(CRAC) by chronic treatment with stress hormones.

Brief Report: Adult Hippocampal Precursor Cells Shorten S‐Phase and Total Cell Cycle Length During Neuronal Differentiation

Cell cycle analyses of adult hippocampal neural stem and precursor cells in vivo are challenging, as there is no temporal or local discrimination of different precursor cell populations. All commonly used techniques to determine the cell cycle length of proliferating cells in the adult hippocampus do not allow discrimination between different cell types. Here, we introduce a novel procedure to precisely calculate cell cycle phase lengths of distinct precursor cell populations in vivo and thereby demonstrate a large heterogeneity of cell cycle kinetics within the pool of adult hippocampal precursor cells. Proliferating NeuroD1(+) cells exhibited a significantly faster S-phase progression (T(s) = 10.1 ± 0.6 hours) and shorter total cell cycle length (T(c) = 22.6 ± 0.1 hours) than NeuroD1(-) cells (T(s) = 13.5 ± 0.8 hours, T(c) = 27.0 ± 0.5 hours; p < .05). Dividing glial fibrillary acidic protein (GFAP(+)) cells also showed significantly shorter mean T(s) of 9.7 ± 0.6 hours and T(c) of 22.8 ± 0.5 hours compared to the rest of uncommitted NeuroD1(-) precursors (p < .01). Together, NeuroD1(+) neuronal progenitors and mitotic GFAP(+) radial glia-like cells divide significantly faster than amplifying neural progenitor cells by accelerating their S-phase. S-phase duration seems to determine cell cycle length in the adult hippocampus.

Interleukin-1β inhibits the differentiation of hippocampal neural precursor cells into serotonergic neurons

Interleukin-1 beta (IL-1β) is one of pro-inflammatory cytokines. Recent studies have shown that IL-1β impairs hippocampal neurogenesis, mediates proliferation and differentiation of multipotent neural precursor cells (NPCs), and exerts effects of anti-proliferation, anti-neurogenesis, and pro-gliogenesis on embryonic hippocampal NPCs. The aim of this study was to examine the effect of IL-1β on the differentiation of hippocampal NPCs into functional serotonergic neurons, which play important roles in the pathophysiology and treatment of depression. Hippocampal NPCs were prepared from the hippocampus of neonatal rats (within 24h after birth). After three passages and phenotyping, hippocampal NPCs were cultured in a differentiating medium with various concentrations (5, 10, and 20ng/mL) of IL-1β for 7 days. At the endpoint, the serotonergic differentiation of hippocampal NPCs in IL-1β-treated cultures decreased in a dose-dependent manner and this effect was blocked by IL-1ra, an IL-1 receptor antagonist capable of blocking the effects of IL-1 by binding to the same receptor (IL-1R1) without triggering signaling; serotonin in the lysate of the differentiated hippocampal NPCs decreased in IL-1β-treated cultures; and levels of Bcl-2 and phosphorylated extracellular-regulated kinase (pERK) were also lower in differentiated hippocampal NPCs with IL-1β treatment. These results support the hypothesis that IL-1β is an important factor in the stress-associated neuropathology and psychopathology and has relevance to the treatment of depressive symptoms in patients with depression.

Three Chinese herbal medicines promote neuroproliferation in vitro, and reverse the effects of chronic mild stress on behavior, the HPA axis, and proliferation of hippocampal precursor cell in vivo

Ethnopharmacological relevanceThe present study investigated whether Chinese herbal medicines (CHMs) could reverse the effects of chronic mild stress (CMS) in a depression-like mouse model. Materials and methodsThe effects of three Chinese herbals, Rhizome Chuanxiong, Radix Scutellaria and Radix Phellodendri on promoting neuroproliferation were evaluated in vitro first and followed by in vivo study of mice which were received by an experimental setting of CMS for 14 days. The effects of the three CHMs on depression were evaluated using a behavioral test, named a forced swimming test (FST). The possible anti-depressive mechanisms of these three CHMs, including the modulation of HPA axis and promoting the hippocampal precursor cell proliferation, were evaluated by measuring plasma corticosterone levels and BrdU incorporation. ResultsThe in vitro results of MTS assay showed that Rhizome Chuanxiong, Radix Scutellaria and Radix Phellodendri could promote the proliferation of neural stem cells (NSCs) in a concentration-dependent manner. The oral administration of these three CHMs for 14 days reversed not only the elevation of plasma corticosterone levels and body weight loss, but also the decreasing of hippocampal precursor cell proliferation and abnormal behavior in the CMS induced depression-like mouse model. ConclusionThese results indicated that Rhizome Chuanxiong, Radix Scutellaria and Radix Phellodendri have the potential to ameliorate depression. The possible mechanisms were the inhibition of HPA axis hyperactivity and the increasing of hippocampal precursor cell proliferation. These findings supported the multicomponent and multitargeted approach of Chinese herbal medicine.

Activation of different neural precursor populations in the adult hippocampus: Does this lead to new neurons with discrete functions?

Resident populations of stem and precursor cells drive the production of new neurons in the adult hippocampus. Recent discoveries have highlighted that a large proportion of these precursor cells are in fact quiescent and can be activated by distinct neuronal activity under both normal physiological and pathological conditions. As growing evidence indicates that newborn neurons play a critical role in cognitive functions such as learning and memory and in mood regulation, it is paramount that we obtain a better understanding of how the reservoirs of stem and precursor cells are maintained and activated. In this review, we critically examine the roles of key molecular mechanisms that have been shown to regulate hippocampal precursor cells, especially their activation. We believe that understanding the mechanistic details of the activity-driven regulation of precursor cells will equip us with the ability to develop tailored strategies to trigger the generation of new neurons, thereby improving the functional outcomes in various neurological and psychiatric conditions.

Induction of the GABA Cell Phenotype: An In Vitro Model for Studying Neurodevelopmental Disorders

Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD67 (GAD1) expression and may play a role in γ-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD67 regulation may result in GABAergic dysfunction, we have developed an in vitro model in which GABA cells are differentiated from the hippocampal precursor cell line, HiB5. Growth factors, such as PDGF, and BDNF, regulate the GABA phenotype by inducing the expression of GAD67 and stimulating the growth of cellular processes, many with growth cones that form appositions with the cell bodies and processes of other GAD67-positive cells. These changes are associated with increased expression of acetylated tubulin, microtubule-associated protein 2 (MAP2) and the post-synaptic density protein 95 (PSD95). The addition of BDNF, together with PDGF, increases the levels of mRNA and protein for GAD67, as well as the high affinity GABA uptake protein, GAT1. These changes are associated with increased concentrations of GABA in the cytoplasm of “differentiated” HiB5 neurons. In the presence of Ca2+ and K+, newly synthesized GABA is released extracellularly. When the HiB5 cells appear to be fully differentiated, they also express GAD65, parvalbumin and calbindin, and GluR subtypes as well as HDAC1, DAXX, PAX5, Runx2, associated with GAD67 regulation. Overall, these results suggest that the HiB5 cells can differentiate into functionally mature GABA neurons in the presence of gene products that are associated with GAD67 regulation in the adult hippocampus.

Berberine Promotes Axonal Regeneration in Injured Nerves of the Peripheral Nervous System

Berberine, an isoquinoline alkaloid component of Coptidis Rhizoma (goldenthread) extract, has been reported to have therapeutic potential for central nervous system disorders such as Alzheimer's disease, cerebral ischemia, and schizophrenia. We have previously shown that berberine promotes the survival and differentiation of hippocampal precursor cells. In a memory-impaired rat model induced by ibotenic acid injection, the survival of pyramidal and granular cells was greatly increased in the hippocampus by berberine administration. In the present study, we investigated the effects of berberine on neurite outgrowth in the SH-SY5Y neuronal cell line and axonal regeneration in the rat peripheral nervous system (PNS). Berberine enhanced neurite extension in differentiating SH-SY5Y cells at concentrations of 0.25-3 μg/mL. In an injury model of the rat sciatic nerve, we examined the neuroregenerative effects of berberine on axonal remyelination by using immunohistochemical analysis. Four weeks after berberine administration (20 mg/kg i.p. once per day for 1 week), the thickness of remyelinated axons improved approximately 1.4-fold in the distal stump of the injury site. Taken together, these results indicate that berberine promotes neurite extension and axonal regeneration in injured nerves of the PNS.

A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells

Neurogenesis occurs in the hippocampus of the developing and adult brain due to the presence of multipotent stem cells and restricted precursor cells at different stages of differentiation. It has been proposed that they may be of potential benefit for use in cell transplantation approaches for neurodegenerative disorders and trauma. Prolonged release of interleukin-1β (IL-1β) from activated microglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesis and cognitive dysfunction associated with aging, Alzheimer's disease and depression. This study assessed the effect of IL-1β on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. We show that IL-1R1 is expressed on proliferating NPCs and that IL-1β treatment decreases cell proliferation and neurosphere growth. When NPCs were differentiated in the presence of IL-1β, a significant reduction in the percentages of newly-born neurons and post-mitotic neurons and a significant increase in the percentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptor antagonist. These data reveal that IL-1β exerts an anti-proliferative, anti-neurogenic and pro-gliogenic effect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise the consequences of an inflammatory environment during NPC development, and indicate that strategies to inhibit IL-1β signalling may be necessary to facilitate effective cell transplantation approaches or in conditions where endogenous hippocampal neurogenesis is impaired.

Progress in cell grafting therapy for temporal lobe epilepsy.

Temporal lobe epilepsy (TLE), exemplified by complex partial seizures, is recognized in ~30% of epileptic patients. Seizures in TLE are associated with cognitive dysfunction and are resistant to antiepileptic drug therapy in ~35% of patients. Although surgical resection of the hippocampus bestows improved seizure regulation in most cases of intractable TLE, this choice can cause lasting cognitive deficiency and reliance on antiepileptic drugs. Thus, alternative therapies that are proficient in both containing the spontaneous recurrent seizures and reversing the cognitive dysfunction are needed. The cell transplantation approach is promising in serving as an adept alternate therapy for TLE, because this strategy has shown the capability to curtail epileptogenesis when used soon after an initial precipitating brain injury, and to restrain spontaneous recurrent seizures and improve cognitive function when utilized after the occurrence of TLE. Nonetheless, this treatment needs further advancement and rigorous evaluation in animal prototypes of chronic TLE before the conceivable clinical use. It is especially vital to gauge the efficacy of distinct donor cell types, such as the hippocampal precursor cells, γ-aminobutyric acid-ergic progenitors, and neural stem cells derived from diverse human sources (including the embryonic stem cells and induced pluripotent stem cells) for longstanding seizure suppression using continuous electroencephalographic recordings for prolonged periods. Additionally, the identification of the mechanisms underlying the graft-mediated seizure suppression and improved cognitive function, and the development of apt grafting strategies that enhance the anti-seizure and pro-cognitive effects of grafts will be necessary. The goal of this review is to evaluate the progress made hitherto in this area and to discuss the prospect for cell-based therapy for TLE.

Role of Neuronal Ras Activity in Adult Hippocampal Neurogenesis and Cognition

Hippocampal neurogenesis in the adult mammalian brain is modulated by various signals like growth factors, hormones, neuropeptides, and neurotransmitters. All of these factors can (but not necessarily do) converge on the activation of the G protein Ras. We used a transgenic mouse model (synRas mice) expressing constitutively activated G12V-Harvey Ras selectively in differentiated neurons to investigate the possible effects onto neurogenesis. H-Ras activation in neurons attenuates hippocampal precursor cell generation at an early stage of the proliferative cascade before neuronal lineage determination occurs. Therefore it is unlikely that the transgenically activated H-Ras in neurons mediates this effect by a direct, intracellular signaling mechanism. Voluntary exercise restores neurogenesis up to wild type level presumably mediated by brain-derived neurotrophic factor. Reduced neurogenesis is linked to impairments in spatial short-term memory and object recognition, the latter can be rescued by voluntary exercise, as well. These data support the view that new cells significantly increase complexity that can be processed by the hippocampal network when experience requires high demands to associate stimuli over time and/or space.

Neuronal Ras activation inhibits adult hippocampal progenitor cell division and impairs spatial short‐term memory

A large number of endogenous and exogenous factors have been identified to upregulate and downregulate proliferation, differentiation and/or survival of newborn cells in the adult hippocampus. For studying neuronal mechanisms mediating the impact of those factors, we used a transgenic synRas mouse model expressing constitutively activated Valin12-Harvey Ras selectively in differentiated neurons. BrdU injections showed significantly reduced proliferation of new cells within the adult hippocampus of transgenic animals compared with their wild-type siblings. In contrast, the relative survival of newborn cells was increased in synRas mice, although this effect did not fully compensate for diminished proliferation. Inhibition of progenitor cell proliferation and enhancement of cellular survival were more pronounced in males compared with females. Double labelling and doublecortin immunostaining verified that specifically newborn neurons were decreased in synRas mice. Reduced cell generation was observed already 2 h after BrdU pulse injections, identifying an early precursor cell population as target of the inhibitory transgene effect. Differences in proliferation remained stable after 24 h and were specific for the subgranular zone of the dentate gyrus, as subventricular cell generation was not affected supporting a non-cell autonomous effect on neural hippocampal progenitors. Transgene expression only starts with synaptic differentiation and therefore reduced proliferation must represent an indirect secondary consequence of synRas activity in differentiated neurons. This was associated with impaired spatial short-term memory capacities as observed in a radial maze paradigm. Our data suggest that constantly high Ras activity in differentiated neurons downregulates hippocampal precursor cell generation in the neuronal lineage, but is modulated by sex-dependent factors.

NPY augments the proliferative effect of FGF2 and increases the expression of FGFR1 on nestin positive postnatal hippocampal precursor cells, via the Y1 receptor

We have shown that neuropeptide Y (NPY), a peptide neurotransmitter released by hippocampal interneurons, is proliferative for hippocampal neural stem progenitor cells (NSPCs) via the Y1 receptor. Fibroblast growth factor (FGF) 2, released predominantly by astrocytes, is also a powerful mitogen for postnatal and adult NSPCs, via the FGFR1 receptor. Knockout studies show that NPY and FGF2 are individually necessary, but not sufficient, for seizure-induced neurogenesis, suggesting a possible interaction. Here, we examined for interactions between NPY and FGF2 on NSPCs from the postnatal hippocampus and report that the combination of NPY and FGF2 significantly shortens the cell cycle time of nestin positive NSPCs, more than either factor alone. This augmentation of proliferation rate is NPY Y1 receptor mediated, and Y1 receptor activation increases both FGFR1 mRNA and protein in NSPC cultures. NSPCs immunostain for both Y1 and FGFR1 receptors and the interaction is specific for dentate NSPCs. This is the first report of a proliferative factor that augments the proliferative effect of FGF2 and is the first evidence of a positive proliferative interaction between a glial growth factor and a neuronal transmitter, identifying a novel neural activity driven mechanism for modulating the proliferation of hippocampal NSPCs.

Age-related effects on hippocampal precursor cell subpopulations and neurogenesis

Hippocampal neurogenesis continuously declines in the aging brain but only little is known about age-related alterations in the subgranular zone (SGZ) of the dentate gyrus which accommodates different subpopulations of precursor cells. Here, we examined the age-related effects on total number and proliferation rate of distinct precursor cell populations in the dentate gyrus of 3 and 16 months old transgenic pNestin-GFP mice. Following a single injection of bromodeoxyuridine (BrdU) we observed a significant reduction of all proliferating precursor subtypes in aged mice compared to young controls. Stereological analysis further revealed that this decreased proliferation was not only caused by a general reduction in total number of precursor subtypes but also by a subtype-specific alteration of the proliferation rate. Whereas radial glia-like and early neuronal precursor cells demonstrate decreased proliferation rates, no difference was found for doublecortin-positive precursors. Additional long-term experiments further revealed that these age-related alterations in the proliferative zone were accompanied by a strongly decreased neurogenesis while hippocampal function was not impaired.

Tumour necrosis factor-α impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1

Tumour necrosis factor-α (TNFα) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFα treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFα, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFα receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFα when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1.

How DISC1 Regulates Postnatal Brain Development: Girdin Gets In on the AKT

In this issue of Neuron, Kim et al. and Enomoto et al. show that DISC1 plays a key role in regulating postnatal brain development though interaction with Girdin. Girdin in turn regulates AKT signaling. Thus, another facet of the role of DISC1 is established, shedding more light on fundamental brain processes and the developmental basis of major psychiatric disorders.

Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus

To understand the link between peripheral immune activation and neuronal precursor biology, we investigated the effect of T-cell activation on adult hippocampal neurogenesis in female C57Bl/6 mice. A peripheral adaptive immune response triggered by adjuvant-induced rheumatoid arthritis (2 microg/microl methylated BSA) or staphylococcus enterotoxin B (EC(50) of 0.25 microg/ml per 20 g body weight) was associated with a transient increase in hippocampal precursor cell proliferation and neurogenesis as assessed by immunohistochemistry and confocal microscopy. Both treatments were paralleled by an increase in corticosterone levels in the hippocampus 1- to 2-fold over the physiological amount measured by quantitative radioimmunoassay. In contrast, intraperitoneal administration of the innate immune response activator lipopolysaccaride (EC(50) of 0.5 microg/ml per 20 g body weight) led to a chronic 5-fold increase of hippocampal glucocorticoid levels and a decrease of adult neurogenesis. In vitro exposure of murine neuronal progenitor cells to corticosterone triggered either cell death at high (1.5 nM) or proliferation at low (0.25 nM) concentrations. This effect could be blocked using a viral vector system expressing a transdomain of the glucocorticoid receptor. We suggest an evolutionary relevant communication route for the brain to respond to environmental stressors like inflammation mediated by glucocorticoid levels in the hippocampus.