Talk:Neural - Hippocampus Development

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Cite this page: Hill, M.A. (2021, June 15) Embryology Neural - Hippocampus Development. Retrieved from


Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults

Nature. 2018 Mar 15;555(7696):377-381. doi: 10.1038/nature25975. Epub 2018 Mar 7.

Sorrells SF1,2, Paredes MF1,3, Cebrian-Silla A4, Sandoval K1,3, Qi D5, Kelley KW1, James D1, Mayer S1,3, Chang J6, Auguste KI2, Chang EF2, Gutierrez AJ7, Kriegstein AR1,3, Mathern GW8,9, Oldham MC1,2, Huang EJ10, Garcia-Verdugo JM4, Yang Z5, Alvarez-Buylla A1,2.


New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved. PMID: 29513649 DOI: 10.1038/nature25975


Evolution of the mammalian dentate gyrus

J Comp Neurol. 2016 Feb 15;524(3):578-94. doi: 10.1002/cne.23851. Epub 2015 Jul 29.

Hevner RF.


The dentate gyrus (DG), a part of the hippocampal formation, has important functions in learning, memory, and adult neurogenesis. Compared with homologous areas in sauropsids (birds and reptiles), the mammalian DG is larger and exhibits qualitatively different phenotypes: 1) folded (C- or V-shaped) granule neuron layer, concave toward the hilus and delimited by a hippocampal fissure; 2) nonperiventricular adult neurogenesis; and 3) prolonged ontogeny, involving extensive abventricular (basal) migration and proliferation of neural stem and progenitor cells (NSPCs). Although gaps remain, available data indicate that these DG traits are present in all orders of mammals, including monotremes and marsupials. The exception is Cetacea (whales, dolphins, and porpoises), in which DG size, convolution, and adult neurogenesis have undergone evolutionary regression. Parsimony suggests that increased growth and convolution of the DG arose in stem mammals concurrently with nonperiventricular adult hippocampal neurogenesis and basal migration of NSPCs during development. These traits could all result from an evolutionary change that enhanced radial migration of NSPCs out of the periventricular zones, possibly by epithelial-mesenchymal transition, to colonize and maintain nonperiventricular proliferative niches. In turn, increased NSPC migration and clonal expansion might be a consequence of growth in the cortical hem (medial patterning center), which produces morphogens such as Wnt3a, generates Cajal-Retzius neurons, and is regulated by Lhx2. Finally, correlations between DG convolution and neocortical gyrification (or capacity for gyrification) suggest that enhanced abventricular migration and proliferation of NSPCs played a transformative role in growth and folding of neocortex as well as archicortex. J. Comp. Neurol. 524:578-594, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

PMID 26179319


Hopx distinguishes hippocampal from lateral ventricle neural stem cells

Stem Cell Res. 2015 Nov;15(3):522-9. doi: 10.1016/j.scr.2015.09.015. Epub 2015 Oct 8.

Li D1, Takeda N1, Jain R1, Manderfield LJ1, Liu F1, Li L1, Anderson SA2, Epstein JA3.


In the adult dentate gyrus (DG) and in the proliferative zone lining the lateral ventricle (LV-PZ), radial glia-like (RGL) cells are neural stem cells (NSCs) that generate granule neurons. A number of molecular markers including glial fibrillary acidic protein (GFAP), Sox2 and nestin, can identify quiescent NSCs in these two niches. However, to date, there is no marker that distinguishes NSC origin of DG versus LV-PZ. Hopx, an atypical homeodomain only protein, is expressed by adult stem cell populations including those in the intestine and hair follicle. Here, we show that Hopx is specifically expressed in RGL cells in the adult DG, and these cells give rise to granule neurons. Assessed by non-stereological quantitation, Hopx-null NSCs exhibit enhanced neurogenesis evident by an increased number of BrdU-positive cells and doublecortin (DCX)-positive neuroblasts. In contrast, Sox2-positive, quiescent NSCs are reduced in the DG of Hopx-null animals and Notch signaling is reduced, as evidenced by reduced expression of Notch targets Hes1 and Hey2, and a reduction of the number of cells expressing the cleaved, activated form of the Notch1 receptor, the Notch intracellular domain (NICD) in Hopx-null DG. Surprisingly, Hopx is not expressed in RGL cells of the adult LV-PZ, and Hopx-expressing cells do not give rise to interneurons of the olfactory bulb (OB). These findings establish that Hopx expression distinguishes NSCs of the DG from those of the LV-PZ, and suggest that Hopx potentially regulates hippocampal neurogenesis by modulating Notch signaling. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved. KEYWORDS: Dentate gyrus; Hippocampus; Hopx; Neural stem cell; Neurogenesis; Notch

PMID 26451648


The cortical hem regulates the size and patterning of neocortex

Development. 2014 Jul;141(14):2855-65. doi: 10.1242/dev.106914. Epub 2014 Jun 19.

Caronia-Brown G1, Yoshida M2, Gulden F1, Assimacopoulos S1, Grove EA3.


The cortical hem, a source of Wingless-related (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon, is the embryonic organizer for the hippocampus. Whether the hem is a major regulator of cortical patterning outside the hippocampus has not been investigated. We examined regional organization across the entire cerebral cortex in mice genetically engineered to lack the hem. Indicating that the hem regulates dorsoventral patterning in the cortical hemisphere, the neocortex, particularly dorsomedial neocortex, was reduced in size in late-stage hem-ablated embryos, whereas cortex ventrolateral to the neocortex expanded dorsally. Unexpectedly, hem ablation also perturbed regional patterning along the rostrocaudal axis of neocortex. Rostral neocortical domains identified by characteristic gene expression were expanded, and caudal domains diminished. A similar shift occurs when fibroblast growth factor (FGF) 8 is increased at the rostral telencephalic organizer, yet the FGF8 source was unchanged in hem-ablated brains. Rather we found that hem WNT or BMP signals, or both, have opposite effects to those of FGF8 in regulating transcription factors that control the size and position of neocortical areas. When the hem is ablated a necessary balance is perturbed, and cerebral cortex is rostralized. Our findings reveal a much broader role for the hem in cortical development than previously recognized, and emphasize that two major signaling centers interact antagonistically to pattern cerebral cortex.

PMID 24948604

Neurogenesis in the Septal and Temporal part of the Adult Rat Dentate Gyrus

Hippocampus. 2014 Nov 14. doi: 10.1002/hipo.22388. [Epub ahead of print]

Bekiari C1, Giannakopoulou A, Siskos N, Grivas I, Tsingotjidou A, Michaloudi H, Papadopoulos GC.


Structural and functional dissociation between the septal and the temporal part of the dentate gyrus predispose for possible differentiations in the ongoing neurogenesis process of the adult hippocampus. In the present study, BrdU-dated subpopulations of the rat septal and temporal dentate gyrus (co-expressing GFAP, DCX, NeuN, calretinin, calbindin, S100, caspase-3 or fractin) were quantified comparatively at 2, 5, 7, 14, 21 and 30 days after BrdU administration in order to examine the successive time-frames of the neurogenesis process, the glial or neuronal commitment of newborn cells and the occurring apoptotic cell death. Newborn neurons' migration from the neurogenic subgranular zone to the inner granular cell layer and expression of glutamate NMDA and AMPA receptors were also studied. BrdU immunocytochemistry revealed comparatively higher numbers of BrdU+ cells in the septal part, but stereological analysis of newborn and total granule cells showed an identical ratio in the two parts, indicating an equivalent neurogenic ability, and a common topographical pattern along each part's longitudinal and transverse axis. Similarly, both parts exhibited extremely low levels of newborn glial and apoptotic cells. However, despite the initially equal division rate and pattern of the septal and temporal proliferating cells, their later proliferative profile diverged in the two parts. Dynamic differences in the differentiation, migration and maturation process of the two BrdU-incorporating subpopulations of newborn neurons were also detected, along with differences in their survival pattern. Therefore, we propose that various factors, including developmental date birth, local DG microenvironment and distinct functionality of the two parts may be the critical regulators of the ongoing neurogenesis process, leading the septal part to a continuous, rapid and less disciplined genesis rate, whereas the quiescent temporal microenvironment preserves a quite steady, less demanding neurogenesis process. This article is protected by copyright. All rights reserved. Copyright © 2014 Wiley Periodicals, Inc., a Wiley company. KEYWORDS: BrdU; adult hippocampal neurogenesis; gliogenesis; maturation; septo-temporal axis

PMID 25394554


Collagen XIX is expressed by interneurons and contributes to the formation of hippocampal synapses

J Comp Neurol. 2010 Jan 10;518(2):229-53.

Su J, Gorse K, Ramirez F, Fox MA.

Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia 23298, USA. Abstract Extracellular matrix (ECM) molecules contribute to the formation and maintenance of synapses in the mammalian nervous system. We previously discovered a family of nonfibrillar collagens that organize synaptic differentiation at the neuromuscular junction (NMJ). Although many NMJ-organizing cues contribute to central nervous system (CNS) synaptogenesis, whether similar roles for collagens exist at central synapses remained unclear. In the present study we discovered that col19a1, the gene encoding nonfibrillar collagen XIX, is expressed by subsets of hippocampal neurons. Colocalization with the interneuron-specific enzyme glutamate decarboxylase 67 (Gad67), but not other cell-type-specific markers, suggests that hippocampal expression of col19a1 is restricted to interneurons. However, not all hippocampal interneurons express col19a1 mRNA; subsets of neuropeptide Y (NPY)-, somatostatin (Som)-, and calbindin (Calb)-immunoreactive interneurons express col19a1, but those containing parvalbumin (Parv) or calretinin (Calr) do not. To assess whether collagen XIX is required for the normal formation of hippocampal synapses, we examined synaptic morphology and composition in targeted mouse mutants lacking collagen XIX. We show here that subsets of synaptotagmin 2 (Syt2)-containing hippocampal nerve terminals appear malformed in the absence of collagen XIX. The presence of Syt2 in inhibitory hippocampal synapses, the altered distribution of Gad67 in collagen XIX-deficient subiculum, and abnormal levels of gephyrin in collagen XIX-deficient hippocampal extracts all suggest inhibitory synapses are affected by the loss of collagen XIX. Together, these data not only reveal that collagen XIX is expressed by central neurons, but show for the first time that a nonfibrillar collagen is necessary for the formation of hippocampal synapses.

PMID: 19937713


Early development of neuronal activity in the primate hippocampus in utero

J Neurosci. 2001 Dec 15;21(24):9770-81.

Khazipov R, Esclapez M, Caillard O, Bernard C, Khalilov I, Tyzio R, Hirsch J, Dzhala V, Berger B, Ben-Ari Y.

Institut de Neurobiologie de la Méditerranée/Institut National de la Santé et de la Recherche Médicale (INSERM) U29, Luminy, 13273 Marseille, France. Abstract Morphological studies suggest that the primate hippocampus develops extensively before birth, but little is known about its functional development. Patch-clamp recordings of hippocampal neurons and reconstruction of biocytin-filled pyramidal cells were performed in slices of macaque cynomolgus fetuses delivered by cesarean section. We found that during the second half of gestation, axons and dendrites of pyramidal cells grow intensively by hundreds of micrometers per day to attain a high level of maturity near term. Synaptic currents appear around midgestation and are correlated with the level of morphological differentiation of pyramidal cells: the first synapses are GABAergic, and their emergence correlates with the growth of apical dendrite into stratum radiatum. A later occurrence of glutamatergic synaptic currents correlates with a further differentiation of the axodendritic tree and the appearance of spines. Relying on the number of dendritic spines, we estimated that hundreds of new glutamatergic synapses are established every day on a pyramidal neuron during the last third of gestation. Most of the synaptic activity is synchronized in spontaneous slow ( approximately 0.1 Hz) network oscillations reminiscent of the giant depolarizing potentials in neonatal rodents. Epileptiform discharges can be evoked by the GABA(A) receptor antagonist bicuculline by the last third of gestation, and postsynaptic GABA(B) receptors contribute to the termination of epileptiform discharges. Comparing the results obtained in primates and rodents, we conclude that the template of early hippocampal network development is conserved across the mammalian evolution but that it is shifted toward fetal life in primate.

PMID: 11739585


Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1

Development. 2000 Feb;127(3):469-82.

Galceran J, Miyashita-Lin EM, Devaney E, Rubenstein JL, Grosschedl R.

Howard Hughes Medical Institute, Department of Microbiology, University of California, San Francisco, CA 94143, USA. Abstract Lef1 and other genes of the LEF1/TCF family of transcription factors are nuclear mediators of Wnt signaling. Here we examine the expression pattern and functional importance of Lef1 in the developing forebrain of the mouse. Lef1 is expressed in the developing hippocampus, and LEF1-deficient embryos lack dentate gyrus granule cells but contain glial cells and interneurons in the region of the dentate gyrus. In mouse embryos homozygous for a Lef1-lacZ fusion gene, which encodes a protein that is not only deficient in DNA binding but also interferes with (beta)-catenin-mediated transcriptional activation by other LEF1/TCF proteins, the entire hippocampus including the CA fields is missing. Thus, LEF1 regulates the generation of dentate gyrus granule cells, and together with other LEF1/TCF proteins, the development of the hippocampus.

PMID: 10631168

A local Wnt-3a signal is required for development of the mammalian hippocampus

Development. 2000 Feb;127(3):457-67.

Lee SM, Tole S, Grove E, McMahon AP.

Department of Molecular Biology, The Biolabs, Harvard University, Cambridge, MA 02138, USA. Abstract The mechanisms that regulate patterning and growth of the developing cerebral cortex remain unclear. Suggesting a role for Wnt signaling in these processes, multiple Wnt genes are expressed in selective patterns in the embryonic cortex. We have examined the role of Wnt-3a signaling at the caudomedial margin of the developing cerebral cortex, the site of hippocampal development. We show that Wnt-3a acts locally to regulate the expansion of the caudomedial cortex, from which the hippocampus develops. In mice lacking Wnt-3a, caudomedial cortical progenitor cells appear to be specified normally, but then underproliferate. By mid-gestation, the hippocampus is missing or represented by tiny populations of residual hippocampal cells. Thus, Wnt-3a signaling is crucial for the normal growth of the hippocampus. We suggest that the coordination of growth with patterning may be a general role for Wnts during vertebrate development.

PMID: 10631167

Quantitative morphology of human hippocampus early neuron development

Anat Rec. 1999 Jan;254(1):87-91.

Zaidel DW.

Department of Psychology, University of California at Los Angeles, 90095-1563, USA. Abstract Previous findings in adults revealed significant hemispheric asymmetry in the size of neuronal somata in hippocampal subfield CA2 (the resistant sector) with no age-related changes. A paucity of quantitative data on the developmental status of these protected neurons has led to the investigation of their morphology in comparison to neurons in adjacent subfield CA3, bilaterally. Bilateral coronal sections from postmortem hippocampus, 24 to 76 weeks postmenstrual age (gestational age plus postnatal age), were studied. The neurons were digitized and measured on a computer. Soma size correlated positively and significantly with age in CA2 and CA3, bilaterally. CA2 somata were significantly larger (left, 34%; right, 32%) than adjacent CA3 somata. Variability in soma form or size increased appreciably with age, in both subfields, bilaterally, while variability in soma orientation was weakly correlated with brain growth. The results suggest that in early development there are similarities in hemispheric growth patterns in CA2 and CA3. Large CA2 soma size implies axonal connectivity to distantly located targets very early in development. The results have functional implications, including memory, to brain development.

PMID: 9892421

Development of excitatory circuitry in the hippocampus

J Neurophysiol. 1998 Apr;79(4):2013-24.

Hsia AY, Malenka RC, Nicoll RA.

Neuroscience Graduate Program, University of California, San Francisco, San Francisco, California 94143, USA. Abstract Assessing the development of local circuitry in the hippocampus has relied primarily on anatomic studies. Here we take a physiological approach, to directly evaluate the means by which the mature state of connectivity between CA3 and CA1 hippocampal pyramidal cells is established. Using a technique of comparing miniature excitatory postsynaptic currents (mEPSCs) to EPSCs in response to spontaneously occurring action potentials in CA3 cells, we found that from neonatal to adult ages, functional synapses are created and serve to increase the degree of connectivity between CA3-CA1 cell pairs. Neither the probability of release nor mean quantal size was found to change significantly with age. However, the variability of quantal events decreases substantially as synapses mature. Thus in the hippocampus the developmental strategy for enhancing excitatory synaptic transmission does not appear to involve an increase in the efficacy at individual synapses, but rather an increase in the connectivity between cell pairs.

PMID: 9535965

Gray's Anatomy

"Parallel with but above and in front of the choroidal fissure the medial wall of the cerebral vesicle becomes folded outward and gives rise to the hippocampal fissure on the medial surface and to a corresponding elevation, the hippocampus, within the ventricular cavity. The gray or ganglionic covering of the wall of the vesicle ends at the inferior margin of the fissure is a thickened edge; beneath this the marginal or reticular layer (future white substance) is exposed and its lower thinned edge is continuous with the epithelial invagination covering the choroid plexus (Fig. 656). As a result of the later downward and forward growth of the temporal lobe the hippocampal fissure and the parts associated with it extend from the interventricular foramen to the end of the inferior horn of the ventricle. The thickened edge of gray substance becomes the gyrus dentatus, the fasciola cinerea and the supra- and subcallosal gyri, while the free edge of the white substance forms the fimbria hippocampi and the body and crus of the fornix. The corpus callosum is developed within the arch of the hippocampal fissure, and the upper part of the fissure forms, in the adult brain, the callosal fissure on the medial surface of the hemisphere."