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Neurogenesis in Human Hippocampus: Implications for Alzheimer Disease Pathogenesis

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Abstract

Hippocampal neurogenesis, the innate capacity of stem cells in the hippocampus to generate new neurons throughout life, is attracting interest in neurodegenerative disease research as an indicator of neuroplasticity and therefore treatment. Conditions that improve cognitive output and increase neurogenesis are associated with a decreased incidence of Alzheimer disease (AD), and conditions that lead to reduced cognition and neurogenesis are associated with increases in the incidence of AD. Therefore, hippocampal neurogenesis may be of particular relevance in the development of AD, and the modulation of this process can afford an important therapeutic avenue. Nevertheless, apparent contradictions across studies examining all factors of hippocampal neurogenesis in AD have led to a confusing state of affairs regarding the role of this process in the disease, as aberrant cell cycle activation has been advanced as an early pathogenic factor in the development of AD. The objective of this review is to critically examine these contradicting reports and provide additional and alternative insights into the function of hippocampal neurogenesis in AD.

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... The intervention is derived from knowledge about neurogenesis and neuroplasticity. [42][43][44] Neurogenesis is the ability to generate new neurons and neuroplasticity is the capacity that neurons have to modify their synaptic structure and form new neural connections. The knowledge that brain neurons are capable of neuroplasticity in the presence of injury can be used as a basis for intervention. ...
... 11,13,44,45 Neurogenesis and neuroplasticity are mechanisms through which the brain may recover from small, silent infarcts andcompensate for periods of oxygen deprivation. 42,44,45 Data from animal and human studies provide promising, preliminary evidence that intensive training to increase sensory stimulation and performance of cognitively challenging activities promotes neuroplasticity and improves cognitive outcomes. 20,40,43,[46][47] Cognitive training interventions based on scientific principles of neuroplasticity have been tested among healthy elders, including persons at risk of age-related cognitive decline.Individuals who received plasticity-based interventions had improved memory, psychomotor speed, reasoning, and IADLs. ...
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... Acute and chronic brain diseases, such as Alzheimer's disease, have acute and chronic responses from the endogenous NSC population. Head injury, epileptic seizures [49] and transient global and focal ischemia [50][51][52][53] increase hippocampal neurogenesis, but the effects on hippocampal circuit properties and Alzheimer's disease are poorly understood (reviewed by Castellani et al.) [54]. ...
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... Acute and chronic brain diseases, such as Alzheimer's disease, have acute and chronic responses from the endogenous NSC population. Head injury, epileptic seizures [49] and transient global and focal ischemia [50][51][52][53] increase hippocampal neurogenesis, but the effects on hippocampal circuit properties and Alzheimer's disease are poorly understood (reviewed by Castellani et al.) [54]. ...
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The hippocampus is critical for learning and memory and heavily affected in dementia. The presence of stem cells in this structure has led to an increased interest in the phenomenon of adult neurogenesis and its role in hippocampal functioning. Not surprising, investigators of Alzheimer's disease have also evaluated adult neurogenesis due to its responsiveness to hippocampal damage. Although causal relationships have not been established, many factors known to impact neurogenesis in the hippocampus, are implicated in the pathogenesis of AD. Also, adult neurogenesis has been proposed to reflect a "neurogenic reserve" that may determine vulnerability to hippocampal dysfunction and neurodegeneration. Since neurogenesis is modifiable, stimulation of this process, or the potential use of stem cells, recruited endogenously or implanted by transplantation, has been speculated as a possible treatment of neurodegenerative disorders. As the structural and molecular mechanisms governing adult neurogenesis are important for evaluating therapeutic strategies, we will here review collective literature findings and speculate about the future of this field with a focus on findings from Alzheimer's mouse models. Continued research in this area and use of these models is critical for evaluating if neurogenesis based therapeutic strategies will indeed have the potential to aid those with degenerative conditions.
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The beta A4 protein, the major component of the amyloid deposition characterizing Alzheimer's disease, derives from the amyloid protein precursor (APP), an integral membrane protein with soluble derivatives. The function of APP is unknown. Both soluble and membrane-associated human brain APP (10(-10) M) significantly increased (P less than 0.025) neurite length and branching in pheochromocytoma PC12 cells, but did not affect the number of neurites per cell. At higher concentrations, APP was cytotoxic, with a half-maximal concentration of 5 x 10(-9) M. Nerve growth factor (NGF) is known to affect APP expression in vivo and in vitro. Antibodies to APP specifically diminished the effects of NGF on neurite length and branching. Thus APP may act to mediate neurite outgrowth promotion by NGF.
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Age has been reported as a strong risk factor for dementia. Supporting data have been derived mainly from prevalence studies, which had varied criteria and sample compositions that precluded direct comparisons, especially among those aged 85 years and older. Data regarding rates of dementia are presented based on 85 incident cases in the Bronx (NY) Aging Study, a prospective study of 488 initially nondemented, old old persons (mean age on entry, 79 years). Overall, the incidence rate over 8 years of follow-up for all-cause dementia was 3.4 per 100 per year (43% Alzheimer's disease, 30% mixed Alzheimer's and vascular, and 27% other). Incidence rose significantly, irrespective of gender, as subjects were followed up through three age intervals— ages 75 to 79 years (1.3/100 per year), 80 to 84 years (3.5), and 85 years and older (6.0). The comparable age-associated prevalence rates of dementia were 3.7%, 12.2%, and 23.9%, respectively, with an overall period prevalence of 22.8%. Additionally, there was a threefold greater mortality associated with dementia. In conclusion, despite the shortened life expectancy of demented persons, dementia is a highly prevalent condition among those aged 85 years and older. Public policy attention is warranted, since this group is the fastest growing population subgroup. (Arch Intern Med. 1991;151:989-992)
Article
The form of the secreted amyloid beta-protein precursor which contains the protease inhibitor sequence is mitogenic for Swiss 3T3 cells, while the precursor molecule lacking the protease inhibitor domain is not. A ten-fold stimulation of DNA synthesis occurs at 8 x 10(-9) M protein.
Article
Alzheimer's disease is the most significant of the age-related diseases of the brain. The incidence of Alzheimer's at age 80 is twenty-fold that at age 60 years. In one study the incidence at age 80 surpassed that of stroke. Three major advances have occurred in regard to Alzheimer's disease: (1) clinical diagnosis has markedly improved and now approaches 90% accuracy; (2) understanding of the biology of Alzheimer's has increased with delineation of specific fibrous protein abnormalities and identification of the amyloid precursor gene and the gene linked to familial Alzheimer's, both genes being located on chromosome 21; and (3) there have been advances in the correlation of specific nerve cell involvement and neurotransmitter changes with physiological (position emission tomography), behavioural and neuropsychological manifestations.
Article
Research regarding the possible association between Alzheimer's disease and a history of depression has been inconclusive. Using a case-control design, we assessed the strength of the association between reported history of depression and onset of Alzheimer's disease. We enrolled probable Alzheimer's disease cases (N = 294), who were ascertained and diagnosed by our Alzheimer's Disease Patient Registry, and randomly selected nondemented controls (N = 300) of similar age and gender from the same base population. The mean age (for cases) was 78.5 years. Informants provided data regarding history of depression. "Treated depression" was defined as depression for which a physician/psychologist consultation, medication, or hospitalization had occurred. Restricting treated depression to exclude primary loss or grief reactions, we found a modest association with Alzheimer's disease [odds ratio (OR) = 1.8; 95% confidence interval (CI) = 0.9-3.5] after adjusting for gender, age, education, and type of informant. When these data were stratified by depression onset year, we observed an odds ratio of 2.0 (95% CI = 0.9-4.6) for depression occurring more than 10 years before the onset of dementia symptoms, and an OR of 0.9 (95% CI = 0.2-3.0) for depression onset within 10 years of the onset of dementia symptoms. Thus, depressive episodes occurring well before dementia symptom onset appear to increase the risk of Alzheimer's disease.
Article
The subventricular zone of the postnatal forebrain produces mainly glia, although it supports limited neurogenesis. To determine whether the subventricular zone is positionally specified, the phenotype and destination of the progeny of subventricular zone cells along the anterior-posterior axis of the lateral ventricles were analyzed. A retroviral lineage tracer containing the E. coli reporter gene lacZ was injected into different parts of the subventricular zone of neonatal rat pups, and at various times thereafter, the expression of beta-galactosidase was detected histochemically or immunohistochemically in the descendants of infected cells. A discrete region of the anterior part of the subventricular zone (SVZa) generated an immense number of neurons that differentiated into granule cells and periglomerular cells of the olfactory bulb-the two major types of interneurons. Thus, the SVZa appears to constitute a specialized source of neuronal progenitor cells. To reach the olfactory bulb, neurons arising in the SVZa migrate several millimeters along a highly restricted route. Guidance cues must be involved to prohibit widespread dispersion of these migrating neurons.
Article
To explore the relationship between age, education, and occupation with dementia among African Americans. Community-based survey to identify subjects with and without evidence of cognitive impairment and subsequent diagnostic evaluation of a stratified sample of these subjects using formal diagnostic criteria for dementia. Urban neighborhoods in Indianapolis, Ind. A random sample of 2212 African Americans aged 65 years and older residing in 29 contiguous census tracts. Subjects's scores on the Community Screening Instrument for Dementia (CSI-D), formal diagnostic clinical assessments for dementia, years of education, rural residence, primary occupation, self-reported disease, and alcohol and smoking history. Caseness was defined by four separate criteria: (1) cognitive impairment as defined by the subject's performance on the CSI-D cognitive scale; (2) cognitive impairment as defined by the total CSI-D score that included a relative's assessment of the subject's functional abilities; (3) dementia as defined by explicit diagnostic criteria; and (4) possible or probable Alzheimer's disease as defined by explicit diagnostic criteria. The mean age was 74 years (age range, 65 to 100 years), 65% of subjects were women, the mean education was 9.6 years (age range, 0 to 16 years), 98% of the subjects were literate, and 32% reported living in a rural area until age 19 years. Service, domestic, and production occupations accounted for 55.2% of the subjects' primary occupations with a mean of 25.8 years (range, 1 to 75 years) in the primary occupation. Years of education, rural residence to age 60 years, and primary occupation were highly correlated. Caseness defined by any of the four criteria was associated with functional impairment, but the frequency of impairment increased with increasing diagnostic specificity. Age, education, and rural residence to age 60 years were significantly independently associated with caseness for cognitive impairment, dementia, and Alzheimer's type dementia. White-collar occupation was independently associated only with caseness for cognitive impairment. History of stroke was associated with caseness for cognitive impairment and dementia but not Alzheimer's disease, while history of smoking was negatively correlated with Alzheimer's disease. Education was independently associated with cognitive impairment and dementia among a representative community-based sample of African Americans and the association remains significant across a variety of sensitivity analyses designed to control for measurement and confounding biases. The potential protective role of education against the development of dementia among African Americans deserves further evaluation.
Article
Cognitive deficits are common in Parkinson's disease (PD), but the pathophysiology and relationship to Alzheimer's disease (AD) are not understood. We used a case-control format to investigate putative risk factors for the development of dementia in patients with Parkinson's disease. We compared 52 cognitively intact patients with PD to 43 PD patients with dementia with regard to factors previously suggested as relevant to either AD or PD. Multiple logistic regression yielded the following significant predictors of dementia in PD: lack of education (less than a high school graduate) (OR 21); severity of motor deficit (UPDRS total motor score greater than 20; OR 6.34), and PD onset at greater than 60 years of age (OR 4.12). The predictive probability of dementia in our subjects when all three variables were positive was 97.9%. We conclude that education may modify the risk of cognitive decline in PD. Protective effects of educational attainment, independent of dementia etiology, may be due to greater functional brain reserve.
Article
Proliferative cells lining the cerebral ventricles generate all of the phenotypically diverse neurons of the adult cortex. Recent evidence indicates that cell cycle events of neuronal precursor cells are under the influence of neurotransmitters and a variety of signaling factors. The newly discovered environmental factors that regulate neurogenesis promise to expand our understanding of the mechanisms responsible for cerebral malformations and disorders of cortical organization.
Article
A qualitative and quantitative evaluation of adult neurogenesis in the telencephalon of a lizard was conducted using [3H]thymidine autoradiography and immunocytochemical detection of 5'-bromodeoxyuridine (BrdU). The sites of cell proliferation, the fate, and the phenotype of cells born in adulthood were determined by short and long survival experiments (7 and 30 days). Adult specimens of the Moorish gecko, Tarentola mauritanica (Sauria, Gekkonidae), received subcutaneous injections of either BrdU or [3H]thymidine. Seven days after BrdU administration most labelled cells were in the walls (ventricular zone; VZ) of the lateral ventricles, particularly close to the sulcal zones. Labelled cells in the VZ of other ventricles were practically absent. Following 30 days, labelled cells outside the VZ were seen in most telencephalic regions: olfactory bulbs (OB), medial, dorsal, and lateral cortices (MC, DC, LC), anterior dorsal ventricular ridge (ADVR), nucleus sphericus (NS), and striatum (St). Electron microscopic examination of [3H]thymidine labelled cells found in these areas revealed their neuronal identity. No labelled neurons were detected in the dorsomedial cerebral cortex (DMC), septum (Sp), or elsewhere in the telencephalon. We conclude that neurogenesis occur in most regions of the adult lizard telencephalon. The most intense neuronal production occurs in the MC. Other telencephalic regions, such as the OB, ADVR, and NS, also show a considerable rate of adult neurogenesis. We infer from our results that the new neurons are born in the walls of the lateral ventricles and then migrate to their destinations. Furthermore, we report some evidence suggesting that neurons formed in adulthood in the olfactory bulbs are generated in the distant proliferative VZ. The functional significance of neurogenesis in the telencephalon of adult lizards is unclear, but it seems to be restricted to areas that have been implicated in olfactory plasticity, learning, and memory.
Article
Neurogenesis continues throughout adulthood in discrete regions. Proliferative zones include the subependymal zone, from where progenitors migrate along the rostral migratory pathway to differentiate into neurons in the olfactory bulb, and the hippocampal subgranular zone, where they migrate and differentiate into granule neurons. Progenitors isolated from adult subependymal zone exhibit in vitro neurogenesis when stimulated with epidermal or fibroblast growth factor. Cultured adult rat hippocampal progenitors (AHPs) grafted to adult rat hippocampus show site-specific neuronal differentiation. Here we investigate determinants of multipotentiality in the adult central nervous system, by grafting AHPs into homotypic (hippocampus) or heterotypic (the rostral migratory pathway) neurogenic sites or a heterotypic, non-neurogenic site (the cerebellum). We found that grafts into neurogenic, but not nonneurogenic sites, showed neuronal differentiation. Furthermore, AHPs grafted in the rostral migratory pathway migrated into the olfactory bulb, differentiating into tyrosine-hydroxylase-positive neurons, a non-hippocampus phenotype. These results reveal that AHP populations can respond to persistent neuronal differentiation cues in the adult central nervous system.
Article
Various mutations in the amyloid protein precursor and presenilin genes can lead to early onset, autosomal Alzheimer's disease. A series of mis-sense mutations (with one exception) in each of these genes has been shown to cause disease in a fully penetrant fashion. It has recently been shown, both in vivo and in model systems, that tissues expressing these mutations have increased production of amyloid (A beta) ending at residue 42. It has also recently been shown that this form of A beta is deposited early and selectively in the disease process and is more fibrillogenic in vitro. It is argued that these genetic and molecular biological data provide strong support for the veracity of the 'amyloid cascade hypothesis' for disease pathogenesis, and that this hypothesis offers a coherent framework for drug discovery.
Article
Approximately 10% of cases of Alzheimer's disease are familial and associated with autosomal dominant inheritance of mutations in genes encoding the amyloid precursor protein, presenilin 1 (PS1) and presenilin 2 (PS2). Mutations in PS1 are linked to about 25% of cases of early-onset familial Alzheimer's disease. PS1, which is endoproteolytically processed in vivo, is a multipass transmembrane protein and is a functional homologue of SEL-12, a Caenorhabditis elegans protein that facilitates signalling mediated by the Notch/LIN-12 family of receptors. To examine potential roles for PS1 in facilitating Notch-mediated signalling during mammalian embryogenesis, we generated mice with targeted disruptions of PS1 alleles (PS1-/- mice). PS1-/- embryos exhibited abnormal patterning of the axial skeleton and spinal ganglia, phenotypes traced to defects in somite segmentation and differentiation. Moreover, expression of mRNA encoding Notch1 and Dll1 (delta-like gene 1), a vertebrate Notch ligand, is markedly reduced in the presomitic mesoderm of PS1-/- embryos compared to controls. Hence, PS1 is required for the spatiotemporal expression of Notch1 and Dll1, which are essential for somite segmentation and maintenance of somite borders.
Article
Presenilin-1 (PS1) is the major gene responsible for early-onset familial Alzheimer's disease (FAD). To understand the normal function of PS1, we have generated a targeted null mutation in the murine homolog of PS1. We report that PS1-/- mice die shortly after natural birth or Caesarean section. The skeleton of homozygous mutants is grossly deformed. Hemorrhages occur in the CNS of PS1 null mutants with varying location, severity, and time of onset. The ventricular zone of PS1-/- brains is markedly thinner by embryonic day 14.5, indicating an impairment in neurogenesis. Bilateral cerebral cavitation caused by massive neuronal loss in specific subregions of the mutant brain is prominent after embryonic day 16.5. These results show that PS1 is required for proper formation of the axial skeleton, normal neurogenesis, and neuronal survival.
Article
To address genetic influences on hippocampal neurogenesis in adult mice, we compared C57BL/6, BALB/c, CD1(ICR), and 129Sv/J mice to examine proliferation, survival, and differentiation of newborn cells in the dentate gyrus. Proliferation was highest in C57BL/6; the survival rate of newborn cells was highest in CD1. In all strains approximately 60% of surviving newborn cells had a neuronal phenotype, but 129/SvJ produced more astrocytes. Over 6 days C57BL/6 produced 0.36% of their total granule cell number of 239,000 as new neurons, BALB/c 0.30% of 242,000, CD1 (ICR) 0.32% of 351,000, and 129/SvJ 0.16% of 280,000. These results show that different aspects of adult hippocampal neurogenesis are differentially influenced by the genetic background.
Article
New neurons are continuously born in the dentate gyrus of the adult mouse hippocampus, and regulation of adult neurogenesis is influenced by both genetic and environmental determinants. Mice of the 129/SvJ strain have significantly less hippocampal neurogenesis than other inbred mouse strains [1] and do not perform well in learning tasks. Here, the impact of environmental stimuli on brain plasticity during adulthood of 129/SvJ mice was studied using 'enriched environments' where mice receive complex inanimate and social stimulation [2,3]. In contrast to our earlier reports on mice of the C57BL/6 strain - which are competent in learning tasks and in which environmental stimulation did not influence cell proliferation [4,5] - environmentally stimulated 129/SvJ mice were found to have twice as many proliferating cells in the dentate gyrus compared with mice in standard housing. Environmental stimulation fostered the survival of newborn cells in 129/SvJ mice; this effect had also been seen in C57BL/6 mice. Phenotypic analysis of the surviving cells revealed that environmental stimulation resulted in 67% more new neurons. In combination with our earlier results, these data indicate a differential impact of inheritable traits on the environmental regulation of adult hippocampal neurogenesis. In addition, we observed behavioral changes in environmentally stimulated 129/SvJ mice.
Article
Neurogenesis persists in the adult dentate gyrus of rodents throughout the life of the organism. The factors regulating proliferation, survival, migration, and differentiation of neuronal progenitors are now being elucidated. Cells from the adult hippocampus can be propagated, cloned in vitro, and induced to differentiate into neurons and glial cells. Cells cultured from the adult rodent hippocampus can be genetically marked and transplanted back to the adult brain, where they survive and differentiate into mature neurons and glial cells. Although multipotent stem cells exist in the adult rodent dentate gyrus, their biological significance remains elusive.
Article
The granule cell population of the dentate gyrus is produced predominantly during the postnatal period in rats. Previous studies have shown that experimental increases in the levels of adrenal steroids suppress the proliferation of granule cell precursors during the first postnatal week, the time of maximal neurogenesis in the dentate gyrus. These findings raise the possibility that stressful experiences that elevate adrenal steroid levels may inhibit the production of granule neurons, and thus alter the development of the dentate gyrus. To test this possibility, we exposed naive rat pups to the odors of a known predator, adult male rats, and examined both plasma corticosterone levels and the number of 3H-thymidine labeled cells in the dentate gyrus. A single exposure of rat pups to adult male rat odor elevated corticosterone levels immediately and diminished the number of 3H-thymidine labeled cells in the granule cell layer by 24 h later. These results suggest that stressful experiences suppress the production of granule neurons in the developing dentate gyrus.
Article
Alzheimer's disease or dementia of the Alzheimer's type (AD/DAT) is one of the most common dementia conditions and it amounts to over 40-90% of dementia cases among elderly and old patients. Epidemiological studies in this area make a great contribution to the study of the etiology and risk factors of AD/DAT). The collaborative reanalysis of AD/DAT prevalence and incidence in EEC countries ("EURODERM" programme) shows that the overall European age-specific prevalence of AD does not differ greatly. There was an exponential increase in age-specific AD/DAT prevalence was found with age, as evidenced by the studies made in Russia. Sex-specific prevalence and incidence of AD/DAT are unclear since the fact that the condition more often occurs in elderly women than in men of the same age has not been confirmed. The data on risk factors obtained in cohort and case-control studies of AD/DAT have been analyzed. Progress in molecular genetics has identified 3 genes that are responsible for the occurrence of familial forms of the disease. The gene of apolipoprotein E on chromosome 19 is recognized to be the major genetic risk factor of late AD/DAT. The role of gene mutations in the trigger mechanisms of sporadic BA/DAT is also discussed. The environmental risk factors of AD/DAT include brain injury, viral infections, neutroxic chemicals, various immunological and hormonal disorders. The protective role of such factors as long-term use of nonsteroid antiinflammatory agents and estrogens is discussed. The involvement of nicotine dependence in the pathogenesis and the role of smoking as a possible protective factor are the subject of discussion. Such factors as education levels, occupation, stresses are widely discussed, although their role is considered to be controversial. The Russian study revealed the influence of chronic stress on AD development. The authors consider that chronic stress may play an important role in AD/DAT progression.
Article
Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.
Article
Thousands of hippocampal neurons are born in adulthood, suggesting that new cells could be important for hippocampal function. To determine whether hippocampus-dependent learning affects adult-generated neurons, we examined the fate of new cells labeled with the thymidine analog bromodeoxyuridine following specific behavioral tasks. Here we report that the number of adult-generated neurons doubles in the rat dentate gyrus in response to training on associative learning tasks that require the hippocampus. In contrast, training on associative learning tasks that do not require the hippocampus did not alter the number of new cells. These findings indicate that adult-generated hippocampal neurons are specifically affected by, and potentially involved in, associative memory formation.
Article
The subgranule zone of the dentate gyrus in rats has been shown to be proliferative into adulthood and senescence. However, the connectivity of newly generated, identified neurons in the adult has not been definitively described. In the present study, 9 weeks after a series of intraperitoneal injections of 5-bromo-2'-deoxyuridine (BrdU), animals received stereotaxic iontophoretic injections of Fluoro-Gold (FG) into field CA3. Three weeks after FG injections, sections were analyzed for BrdU immunoreactivity (proliferative label), FG retrograde label, and either calbindin-D28k or synaptophysin immunohistochemistry. A large proportion (up to 44%) of BrdU-labeled cells in the dentate gyrus within regions of FG retrograde label incorporated FG. All of the doubly labeled (BrdU-FG) neurons also immunolabeled with the antibody to calbindin-D28k. Many doubly labeled (BrdU-FG) cells were also surrounded in three planes by synaptophysin immunoreactivity. We conclude that newly generated neurons in the dentate gyrus have the correct immunohistochemical profile, send appropriate axonal projections to field CA3, and are surrounded by profiles containing synaptic vesicle proteins.