Dynamic interplay between GABAergic networks and developing neurons in the adult hippocampus

Neurogenesis is a powerful mechanism for structural and functional remodeling that occurs in restricted areas of the adult brain. Although different neurotransmitters regulate various aspects of the progression from neural stem cell quiescence to neuronal maturation, GABA is the main player. The developmental switch from excitation to inhibition combined with a heterogeneous population of GABAergic interneurons that target different subcellular compartments provides multiple points for the regulation of development and function of new neurons. This complexity is enhanced by feedback and feedforward networks that act as sensors and controllers of circuit activity, impinging directly or indirectly onto developing granule cells and, subsequently, on mature neurons. Newly generated granule cells ultimately connect with input and output partners in a manner that is largely sculpted by the activity of local circuits.     

Genetically targeting new neurons in the adult hippocampus

Neurogenesis, the birth of new neu-rons from neural stem cells, is known to occur throughout life in two specific regions of the adult mammalian brain, the sub...     

NMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted-In-Schizophrenia 1 (DISC1)

In the mammalian brain, new neurons are continuously generated throughout life in the dentate gyrus (DG) of the hippocampus. Previous studies have established that newborn neurons migrate a short distance to be integrated into a pre-existing neuronal circuit in the hippocampus. How the migration of newborn neurons is governed by extracellular signals, however, has not been fully understood. Here, we report that NMDA receptor (NMDA-R)-mediated signaling is essential for the proper migration and positioning of newborn neurons in the DG. An intraperitoneal injection of the NMDA-R antagonists, memantine, or 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) into adult male mice caused the aberrant positioning of newborn neurons, resulting in the overextension of their migration in the DG. Interestingly, we revealed that the administration of NMDA-R antagonists leads to a decrease in the expression of Disrupted-In-Schizophrenia 1 (DISC1), a candidate susceptibility gene for major psychiatric disorders such as schizophrenia, which is also known as a critical regulator of neuronal migration in the DG. Furthermore, the overextended migration of newborn neurons induced by the NMDA-R antagonists was significantly rescued by exogenous expression of DISC1. Collectively, these results suggest that the NMDA-R signaling pathway governs the migration of newborn neurons via the regulation of DISC1 expression in the DG.     

Characterization of N-methyl-D-aspartate-evoked taurine release in the developing and adult mouse hippocampus

Taurine is an inhibitory amino acid acting as an osmoregulator and neuroromodulator in the brain, with neuroprotective properties. The ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) greatly potentiates taurine release from brain preparations in both normal and ischemic conditions, the effect being particularly marked in the developing hippocampus. We now characterized the regulation of NMDA-stimulated taurine release from hippocampal slices from adult (3-month-old) and developing (7-day-old) mouse using a superfusion system. The NMDA-stimulated taurine release was receptor-mediated in both adult and developing mouse hippocampus. In adults, only NO-generating compounds, sodium nitroprusside, S-nitroso-N-acetylpenicillamine and hydroxylamine reduced the release, as did also NO synthase inhibitors, 7-nitroindazole and nitroarginine, indicating that the release is mediated by the NO/cGMP pathway. On the other hand, the regulation of the NMDA-evoked taurine release proved to be somewhat complex in the immature hippocampus. It was not affected by the NOergic compounds, but enhanced by the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate and adenosine receptor A(1) agonists, N(6)-cyclohexyladenosine and R(-)N(6)-(2-phenylisopropyl)adenosine in a receptor-mediated manner. The activation of both ionotropic 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors and metabotropic glutamate group I receptors also enhanced the evoked release. The NMDA-receptor-stimulated taurine release could be a part of the neuroprotective properties of taurine, being important particularly under cell-damaging conditions in the developing hippocampus and hence preventing excitotoxicity.     

Immunohistochemical analysis of Disc1 expression in the developing and adult hippocampus

In recent years, Disrupted-In-Schizophrenia 1 (DISC1) has emerged as one of the most promising candidate genes whose disruption confers an increased risk for schizophrenia. Cell biology studies have implicated DISC1 in key neurodevelopmental processes including neurite outgrowth and neuronal migration. In situ hybridization analysis has revealed that Disc1 is expressed in the hypothalamus, olfactory bulbs, the developing cerebral cortex and the hippocampus. The hippocampus is of particular interest because abnormalities in hippocampal volume and function have been consistently reported in schizophrenics. Moreover, DISC1 mutations have been associated with abnormal activation of the hippocampus in humans. Given the involvement of the hippocampus in the pathophysiology of schizophrenia, there is an intriguing possibility that disruption of DISC1 may increase schizophrenia susceptibility by altering the normal development and function of the hippocampus. In order to contribute to our understanding of DISC1's role in the hippocampus, we have performed a detailed analysis of the Disc1 expression pattern in the mouse hippocampus throughout development. We report that Disc1 is expressed throughout the hippocampus during embryonic development, with expression becoming increasingly specialized in Ammon's horn and dentate gyrus granule cells within the first postnatal week. This expression pattern remains consistent into adulthood, with a noted decrease in Disc1 expression in the adult CA1. Disc1 is also expressed in proliferating cells in the adult subgranular zone, as well as in a subset of GABAergic interneurons. Our results are the first report of a detailed immunohistochemical analysis of the ontogeny of Disc1 expression within the hippocampus.     

Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain

Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.     

Pioneer GABA cells comprise a subpopulation of hub neurons in the developing hippocampus

Connectivity in the developing hippocampus displays a functional organization particularly effective in supporting network synchronization, as it includes superconnected hub neurons. We have previously shown that hub network function is supported by a subpopulation of GABA neurons. However, it is unclear whether hub cells are only transiently present or later develop into distinctive subclasses of interneurons. These questions are difficult to assess given the heterogeneity of the GABA neurons and the poor early expression of markers. To circumvent this conundrum, we used "genetic fate mapping" that allows for the selective labeling of GABA neurons based on their place and time of origin. We show that early-generated GABA cells form a subpopulation of hub neurons, characterized by an exceptionally widespread axonal arborization and the ability to single-handedly impact network dynamics when stimulated. Pioneer hub neurons remain into adulthood, when they acquire the classical markers of long-range projecting GABA neurons.     

Glutamate-agonist-evoked taurine release from the adult and developing mouse hippocampus in cell-damaging conditions

Summary Taurine is a neuromodulator and osmoregulator in the central nervous system, also protecting neural cells against excitotoxicity. The effects of the ionotropic glutamate receptor agonists N-methyl-D-aspartate (NMDA), kainate and 2-amino-3-hydroxy-5-methyl-4-imidazolepropionate (AMPA) on [³H]taurine release from hippocampal slices from 3-month-old and 7-day-old mice were studied in cell-damaging conditions. Neural cell injury was induced by superfusing the slices in hypoxic, hypoglycemic and ischemic conditions and by exposing them to metabolic poisons, free radicals and oxidative stress. The release of taurine was greatly enhanced in these conditions at both ages, except in oxidative stress. In normal conditions the three glutamate agonists potentiated taurine release in the immature hippocampus in a receptor-mediated manner, but kainate receptors did not participate in the regulation in the adults. The ability of the agonists to evoke taurine release varied in the cell-damaging conditions, but the glutamate-receptor-activated release was generally operating in the immature hippocampus. This glutamate-receptor-evoked massive release of taurine could have significant neuroprotective effects, particularly in the developing hippocampus, countering the harmful actions of the simultaneously liberated excitatory amino acids.     

Enhanced release of adenosine under cell-damaging conditions in the developing and adult mouse hippocampus

The inhibitory neuromodulator adenosine has been thought to act as an endogenous neuroprotectant against cerebral ischemia and neuronal damage. The release of preloaded [³H]adenosine from hippocampal slices from developing (7-day-old) and adult (3-month-old) mice was characterized using a superfusion system under various cell-damaging conditions, including hypoxia, hypoglycemia, ischemia, oxidative stress, and the presence of free radicals and metabolic poisons. The release of adenosine was greatly potentiated under the above conditions at both ages, with free radicals, metabolic poisons, and ischemia generally having the strongest stimulatory effects. Depolarization by K⁺ ions (50 mM) could then evoke more release of adenosine only in the immature hippocampus. Omission of Ca²⁺ from the superfusion media had no effect on the ischemia-induced release in the adults, indicating that it occurs by a Ca²⁺-independent system. In contrast, the release in the immature hippocampus was partially dependent on extracellular Ca²⁺. Furthermore, the ischemia-induced adenosine release was reduced in Na⁺-deficient media and enhanced by ouabain at both ages, pointing to the involvement of Na⁺-dependent transporters. The release was also reduced by Cl^– channel blockers, thus indicating that a part of the evoked release occurs through anion channels. Another inhibitory neuromodulator and cell volume regulator, taurine, was seen to enhance adenosine release in ischemia at both ages. The simultaneous release of taurine and adenosine under cell-damaging conditions could constitute an important protective mechanism against excessive amounts of excitatory amino acids, counteracting their harmful effects and preventing excitation from reaching neurotoxic levels.     

Involvement of metabotropic glutamate receptors in taurine release in the adult and developing mouse hippocampus

Summary The inhibitory amino acid taurine has been held to function as an osmoregulator and modulator of neural activity, being particularly important in the immature brain. lonotropic glutamate receptor agonists are known markedly to potentiate taurine release. The effects of different metabotropic glutamate receptor (mGluR) agonists and antagonists on the basal and K⁺-stimulated release of [³H]taurine from hippocampal slices from 3-month-old (adult) and 7-day-old mice were now investigated using a superfusion system. Of group I metabotropic glutamate receptor agonists, quisqualate potentiated basal taurine release in both age groups, more markedly in the immature hippocampus. This action was not antagonized by the specific antagonists of group I but by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX), which would suggest an involvement of ionotropic glutamate receptors. (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated the basal release by a receptor-mediated mechanism in the immature hippocampus. The group II agonist (2S, 2R, 3R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG IV) markedly potentiated basal taurine release at both ages. These effects were antagonized by dizocilpine, indicating again the participation of ionotropic receptors. Group III agonists slightly potentiated basal taurine release, as did several antagonists of the three metabotropic receptor groups. Potassium-stimulated (50 mM K⁺) taurine release was generally significantly reduced by mGluR agents, mainly by group I and II compounds. This may be harmful to neurons in hyperexcitatory states. On the other hand, the potentiation by mGluRs of basal taurine release, particularly in the immature hippocampus, together with the earlier demonstrated pronounced enhancement by activation of ionotropic glutamate receptors, may protect neurons against excitotoxicity.Abbreviations ACPD (1±)-1-aminocyclopentane-trans-1,3-dicarboxylate - AIDA (RS)-1-aminoindan-1,5-dicarboxylate - AMPA 2-amino-3-hydroxy05-methyl-4-isoxazolepropionate - CNQX 6-cyano-7-nitroquinoxaline-2,3-dione - CPPG (RS)-2-cyclopropyl-4-phosphonophenylglycine - DCG IV (2S,2R,3R)-2-(2,3-dicarboxycyclopropyl)glycine - DHPG (S)-3,5-dihydroxyphenylglycine - EGLU (2S)-2-ethylglutamate - L-AP3 L(+)-2-amino-3-phosphonopropionate - L-AP4 L(+)-2-amino-4-phosphonobutyrate - L-AP6 L(+)-2-amino-6-phosphonohexanoate - L-SOP O-phospho-L-serine - MPPG (RS)-2-methyl-4-phosphonophenylglycine - MSOP (RS)-2-methylserine-O-phosphate - MSOPPE (RS)-2-methylserine-O-phosphate monophenyl ester - MTPG (RS)-2-methyl-4-tetrazolylphenylglycine - NBQX 6-nitro-7-sulphamoyl[f]quinoxaline-2,3-dione - NMDA N-methyl-D-aspartate - QA quisqualate - S-3C4H-PG (S)-3-carboxy-4-hydroxyphenylglycine - S-4C-PG (S)-4-carboxyphenylglycine; - S-MCGP (S)-2-methyl-4-carboxyphenylglycine     

Cholinergic neurons in the hippocampus

Summary We report here on cholinergic neurons in the rat hippocampal formation that were identified by immunocytochemistry employing a monoclonal antibody against choline acetyltransferase (ChAT), the acetylcholine-synthesizing enzyme. In general, ChAT-immunoreactive cells were rare, but were observed in all layers of the hippocampus proper and fascia dentata with a preponderance in zones adjacent to the hippocampal fissure and in the part of CA1 bordering the subiculum. All immunoreactive cells found were non-pyramidal neurons. They were relatively small with round or ovoid perikarya, which gave rise to thin spine-free dendrites. These hippocampal neurons were very similar to ChAT-immunoreactive cells in the neocortex of the same animals but were quite different from cholinergic neurons in the basal forebrain, medial septal nucleus, and neostriatum, which were larger and more intensely immunostained.Electron-microscopic analysis of ChAT-immunoreactive cells in the hippocampus and fascia dentata revealed synaptic contacts, mainly of the asymmetric type, on cell bodies and smooth proximal dendrites. The nuclei of the immunoreactive cells exhibited deep indentations, which are characteristic for non-pyramidal neurons.Our results provide evidence for an intrinsic source of the hippocampal cholinergic innervation in addition to the well-established septo-hippocampal cholinergic projection.Dr. C. Léránth is on leave of absence from the First Department of Anatomy, Semmelweis University Medical School, H-1450 Budapest, Hungary     

A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain

Active adult neurogenesis occurs in discrete brain regions of all mammals and is widely regarded as a neuronal replacement mechanism. Whether adult-born neurons make unique contributions to brain functions is largely unknown. Here we systematically characterized synaptic plasticity of retrovirally labeled adult-born dentate granule cells at different stages during their neuronal maturation. We identified a critical period between 1 and 1.5 months of the cell age when adult-born neurons exhibit enhanced long-term potentiation with increased potentiation amplitude and decreased induction threshold. Furthermore, such enhanced plasticity in adult-born neurons depends on developmentally regulated synaptic expression of NR2B-containing NMDA receptors. Our study demonstrates that adult-born neurons exhibit the same classic critical period plasticity as neurons in the developing nervous system. The transient nature of such enhanced plasticity may provide a fundamental mechanism allowing adult-born neurons within the critical period to serve as major mediators of experience-induced plasticity while maintaining stability of the mature circuitry.     

Functional consequences of adult malnutrition in developing countries: a review

Credible concepts of malnutrition depend critically on evidence that functional impairment differentiates variation in size from unacceptable abnormality. This paper reviews functional studies on capacity for work, mortality, reproductive outcomes, competitive success, and cultural preferences. Future research priorities should include the comparative significance of simple physical dimensions in distinct ethnic groups for long-term biological and socioeconomic outcomes, and the relationships between the biological and cultural significance of variation in physique.     

Neurogenesis in the adult hippocampus

New neurons continue to be generated in two privileged areas of the adult brain: the dentate gyrus of the hippocampal formation and the olfactory bulb. Adult neurogenesis has been found in all mammals studied to date, including humans. The process of adult neurogenesis encompasses the proliferation of resident neural stem and progenitor cells and their subsequent differentiation, migration, and functional integration into the pre-existing circuitry. This article summarizes recent findings regarding the developmental steps involved in adult hippocampal neurogenesis and the possible functional roles that new hippocampal neurons might play.     

Functional restoration of acoustic units and adult‐generated neurons after hypothalamic lesion

The hypothalamus of the adult ring dove contains acoustic units that respond to species‐specific coo vocalization. Loss of nest coo leads to unsuccessful breeding. However, the recovery of nest coo in some doves suggests that these units are capable of self‐renewal. We have previously shown that lesioning the hypothalamus generates the addition of new neurons at the lesioned area. In this study, we sought to determine whether lesion‐induced new neurons are involved in the recovery of coo‐responsive units. We systematically recorded electrical activity in the ventromedial nucleus (VMN) of the hypothalamus, before and after lesion, for varying periods up to 3 months. Recordings were made when the birds were at rest (spontaneous discharge) and when the birds were exposed to acoustic stimulations (evoked discharge). Concurrently, the lesioned area was monitored for changes in cell types by using bromodeoxyuridine (BrdU) to label newly divided cells and NeuN to identify mature neurons. For 1 month after lesion, there was no sign of electrical activity, and only BrdU‐labeled cells were present. When the first electrical activity occurred, it displayed abnormal spontaneous bursting patterns. The mature discharge patterns (both spontaneous and evoked) occurred after detection of BrdU⁺/NeuN⁺ double‐labeled cells 2–3 months postlesion and were similar to those found in intact and sham‐lesioned birds. Double‐labeled cells bore morphologic characteristics of a neuron and were confirmed with z‐stack analysis using confocal laser scanning microscopy. Moreover, double‐labeled cells were not stained for glial fibrillary acidic protein (GFAP), suggesting that they were neurons. The number of coo‐responsive units was significantly correlated with that of BrdU⁺/NeuN⁺ cells. Furthermore, the marker for recording sites revealed that coo‐responsive units were colocalized with BrdU⁺/NeuN⁺ cells. Taken together, the evidence strongly suggests that lesion‐induced addition of new neurons promotes the functional recovery of the adult hypothalamus. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 197–213, 2004