Time Course Of Maturation Research Articles

Developmental Syngap1 haploinsufficiency in medial ganglionic eminence-derived interneurons impairs auditory cortex activity, social behavior and extinction of fear memory.

Mutations in SYNGAP1, a protein enriched at glutamatergic synapses, cause intellectual disability associated with epilepsy, autism spectrum disorder and sensory dysfunctions. Several studies showed that Syngap1 regulates the time course of forebrain glutamatergic synapse maturation; however, the developmental role of Syngap1 in inhibitory GABAergic neurons is less clear. GABAergic neurons can be classified into different subtypes based on their morphology, connectivity and physiological properties. Whether Syngap1 expression specifically in Parvalbumin (PV) and Somatostatin (SST)-expressing interneurons, which are derived from the medial ganglionic eminence, plays a role in the emergence of distinct brain functions remains largely unknown. We used genetic strategies to generate Syngap1 haploinsufficiency in a) prenatal interneurons derived from the medial ganglionic eminence, b) in postnatal PV cells and c) in prenatal SST interneurons. We further performed in vivo recordings and behavioral assays to test whether and how these different genetic manipulations alter brain function and behavior in mice of either sex.Mice with prenatal-onset Syngap1 haploinsufficiency restricted to Nkx2.1-expressing neurons show abnormal cortical oscillations and increased entrainment induced by 40Hz auditory stimulation, but lack of stimulus-specific adaptation. This latter phenotype was reproduced in mice with Syngap1 haploinsufficiency restricted to PV, but not SST, interneurons. Prenatal-onset Syngap1 haploinsufficiency in Nkx2.1-expressing neurons led to impaired social behavior and inability to extinguish fear memories; however, neither postnatal PV- nor prenatal SST-specific mutant mice show these phenotypes. We speculate that Syngap1 haploinsufficiency in prenatal/perinatal PV interneurons may contribute to cortical activity and cognitive alterations associated with Syngap1 mutations.Significance statement Mutations in the human gene cause a form of developmental epileptic encephalopathy associated with intellectual disability, autism and sensory dysfunctions. Several studies have shown that in addition to playing a major role in the synaptic maturation and plasticity of forebrain excitatory neurons, Syngap1 affects GABAergic circuit function as well. Forebrain GABAergic neurons can be divided into different subtypes. Whether Syngap1 expression specifically in distinct interneuron populations and during specific developmental time windows plays a role in the emergence of distinct brain functions remains largely unknown. Here, we report that early, pre or perinatal Syngap1 expression in developing GABAergic neurons derived from the medial ganglionic eminence promotes the development of auditory cortex function, social behavior and ability to extinguish fear memories.

The functional maturity of grafted human pluripotent stem cell derived-islets (hSC-Islets) evaluated by the glycemic set point during blood glucose normalizing process in diabetic mice

Human pluripotent stem cell (hPSCs) derived-pancreatic islets (hSC-islets) are good candidates for cell replacement therapy for patients with diabetes as substitutes for deceased donor-derived islets, because they are pluripotent and have infinite proliferation potential. Grafted hSC-islets ameliorate hyperglycemia in diabetic mice; however, several weeks are needed to normalize the hyperglycemia. These data suggest hSC-islets require maturation, but their maturation process in vivo is not yet fully understood. In this study, we utilized two kinds of streptozotocin (STZ)-induced diabetes model mice by changing the administration timing in order to examine the time course of maturation of hSC-islets and the effects of hyperglycemia on their maturation. We found no hyperglycemia in immune-compromised mice when hSC-islets had been transplanted under their kidney capsules in advance, and STZ was administered 4 weeks after transplantation. Of note, the blood glucose levels of those mice were stably maintained under 100 mg/dl 10 weeks after transplantation; this is lower than the mouse glycemic set point (120–150 mg/dl), suggesting that hSC-islets control blood glucose levels to the human glycemic set point. We confirmed that gene expression of maturation markers of pancreatic beta cells tended to upregulate during 4 weeks after transplantation. Periodical histological analysis revealed that revascularization was observed as early as 1 week after transplantation, but reinnervation in the grafted hSC-islets was not detected at all, even 15 weeks after transplantation. In conclusion, our hSC-islets need at least 4 weeks to mature, and the human glycemic set point is a good index for evaluating ultimate maturity for hSC-islets in vivo.

The p75 Neurotrophin Receptor in Preadolescent Prefrontal Parvalbumin Interneurons Promotes Cognitive Flexibility in Adult Mice

BackgroundParvalbumin (PV)-positive GABAergic (gamma-aminobutyric acidergic) cells provide robust perisomatic inhibition to neighboring pyramidal neurons and regulate brain oscillations. Alterations in PV interneuron connectivity and function in the medial prefrontal cortex have been consistently reported in psychiatric disorders associated with cognitive rigidity, suggesting that PV cell deficits could be a core cellular phenotype in these disorders. The p75 neurotrophin receptor (p75NTR) regulates the time course of PV cell maturation in a cell-autonomous fashion. Whether p75NTR expression during postnatal development affects adult prefrontal PV cell connectivity and cognitive function is unknown. MethodsWe generated transgenic mice with conditional knockout of p75NTR in postnatal PV cells. We analyzed PV cell connectivity and recruitment following a tail pinch by immunolabeling and confocal imaging in naïve mice or following p75NTR re-expression in preadolescent or postadolescent mice using Cre-dependent viral vectors. Cognitive flexibility was evaluated using behavioral tests. ResultsPV cell-specific p75NTR deletion increased both PV cell synapse density and proportion of PV cells surrounded by perineuronal nets, a marker of mature PV cells, in adult medial prefrontal cortex, but not visual cortex. Both phenotypes were rescued by viral-mediated reintroduction of p75NTR in preadolescent, but not postadolescent, medial prefrontal cortex. Prefrontal cortical PV cells failed to upregulate c-Fos following a tail-pinch stimulation in adult conditional knockout mice. Finally, conditional knockout mice showed impaired fear memory extinction learning as well as deficits in an attention set-shifting task. ConclusionsThese findings suggest that p75NTR expression in adolescent PV cells contributes to the fine-tuning of their connectivity and promotes cognitive flexibility in adulthood.

Maturation time course for brainstem auditory evoked potential in preterm and full term infants

Maturation time course for brainstem auditory evoked potential in preterm and full term infants

Heavy metals and metalloids exposure and in vitro fertilization: Critical concerns in human reproductive medicine.

Exposures to heavy metals and metalloids have been associated with decreased fecundity and fertility in couples conceiving via assisted reproduction. Heavy metals and metalloids can alter the homeostasis of critical hormones controlling sexual maturation by binding to critical hormones and receptors. This may disrupt the time course of sexual maturation directly or indirectly affecting reproductive competence in males and females. The present review aims to provide a summarized overview of associations between heavy metal exposure, reproductive concerns, and IVF outcomes. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in Google Scholar, Scopus, EMBASE and PubMed databases. Initial search produced 1,351 articles from which 30 articles were eligible to be included in the systematic review. From our results, 16 articles reported associations between selected heavy metals and IVF outcomes, while 14 articles summarized the role of heavy metals in reproductive concerns. For the studies on IVF outcomes, different human samples were examined for heavy metals. Heavy metals and metalloids (Pb, Hg, Cd, Cr, Mn, As) correlated negatively with oocyte fertilization/pregnancy rates in hair, follicular fluid, serum, urine and seminal plasma samples, while Cd and Hg in whole blood samples showed no associations. For the studies on reproductive concerns, high levels of heavy metals/metalloids were implicated in the following conditions: infertility (Cd, Pb, Ba, U), spontaneous abortion/miscarriage (Pb, Cd, Sb), congenital heart disease (Al, Mg, Cd), PCOS (As, Cd, Hg, Pb), endometriosis (Pb) and uterine leiomyomata (Hg). Taken together, the results of our study suggest that the impact of heavy metals and metalloids exposure on reproductive health may contribute to the failure rates of in vitro fertilization.

Diverse maturity-dependent and complementary anti-apoptotic brakes safeguard human iPSC-derived neurons from cell death

In humans, most neurons are born during embryonic development and have to persist throughout the entire lifespan of an individual. Thus, human neurons have to develop elaborate survival strategies to protect against accidental cell death. We set out to decipher the developmental adaptations resulting in neuronal resilience. We demonstrate that, during the time course of maturation, human neurons install a complex and complementary anti-apoptotic signaling network. This includes i.) a downregulation of central proteins of the intrinsic apoptosis pathway including several caspases, ii.) a shift in the ratio of pro- and anti-apoptotic BCL-2 family proteins, and iii.) an elaborate regulatory network resulting in upregulation of the inhibitor of apoptosis protein (IAP) XIAP. Together, these adaptations strongly increase the threshold for apoptosis initiation when confronted with a wide range of cellular stressors. Our results highlight how human neurons are endowed with complex and redundant preemptive strategies to protect against stress and cell death.

Cortical Thickness and Clinical Findings in Prescholar Children With Autism Spectrum Disorder.

The term autism spectrum disorder (ASD) includes a wide variability of clinical presentation, and this clinical heterogeneity seems to reflect a still unclear multifactorial etiopathogenesis, encompassing different genetic risk factors and susceptibility to environmental factors. Several studies and many theories recognize as mechanisms of autism a disruption of brain development and maturation time course, suggesting the existence of common neurobiological substrates, such as defective synaptic structure and aberrant brain connectivity. Magnetic resonance imaging (MRI) plays an important role in both assessment of region-specific structural changes and quantification of specific alterations in gray or white matter, which could lead to the identification of an MRI biomarker. In this study, we performed measurement of cortical thickness in a selected well-known group of preschool ASD subjects with the aim of finding correlation between cortical metrics and clinical scores to understand the underlying mechanism of symptoms and to support early clinical diagnosis. Our results confirm that recent brain MRI techniques combined with clinical data can provide some useful information in defining the cerebral regions involved in ASD although large sample studies with homogeneous analytical and multisite approaches are needed.

Cumulative Childhood Maltreatment and Executive Functioning in Adulthood

ABSTRACT Maltreatment during childhood has detrimental consequences for survivors. Among children, maltreatment predicts deficits in cognition and impairment in academic and emotional functioning. Although studied extensively in children, the extent to which cognitive deficits are evident in adulthood has been examined to a lesser extent. Executive functioning (EF) is a set of cognitive processes that help to guide behavior toward goals and is characterized by a prolonged maturational time course. As such, it is particularly vulnerable to the effects of early stress, which confers risk for psychopathology. Thus, it is critical to assess the potential impact of childhood trauma on adult EF. The present study sought to assess the impact of a history of childhood maltreatment on EF during adulthood using both self-reported and task-based measures of EF processes. Higher levels of cumulative childhood maltreatment predicted poorer EF. Furthermore, deficits were not accounted for by current symptoms of depression and anxiety, indicating that the impact of childhood maltreatment on cognitive functioning in adulthood is not the result of current internalizing psychopathology.

Development of electrophysiological and morphological properties of human embryonic stem cell-derived GABAergic interneurons at different times after transplantation into the mouse hippocampus.

Transplantation of human embryonic stem cell (hESC)-derived neural progenitors is a potential treatment for neurological disorders, but relatively little is known about the time course for human neuron maturation after transplantation and the emergence of morphological and electrophysiological properties. To address this gap, we transplanted hESC-derived human GABAergic interneuron progenitors into the mouse hippocampus, and then characterized their electrophysiological properties and dendritic arborizations after transplantation by means of ex vivo whole-cell patch clamp recording, followed by biocytin staining, confocal imaging and neuron reconstruction software. We asked whether particular electrophysiological and morphological properties showed maturation-dependent changes after transplantation. We also investigated whether the emergence of particular electrophysiological properties were linked to increased complexity of the dendritic arbors. Human neurons were classified into five distinct neuronal types (Type I-V), ranging from immature to mature fast-spiking interneurons. Hierarchical clustering of the dendritic morphology and Sholl analyses suggested four morphologically distinct classes (Class A-D), ranging from simple/immature to highly complex. Incorporating all of our data regardless of neuronal classification, we investigated whether any electrophysiological and morphological features correlated with time post-transplantation. This analysis demonstrated that both dendritic arbors and electrophysiological properties matured after transplantation.

Maturation of the microglial population varies across mesolimbic nuclei.

Microglia play critical roles during CNS development and undergo dramatic changes in tissue distribution, morphology, and gene expression as they transition from embryonic to neonatal to adult microglial phenotypes. Despite the magnitude of these phenotypic shifts, little is known about the time course and dynamics of these transitions and whether they vary across brain regions. Here, we define the time course of microglial maturation in key regions of the basal ganglia in mice, where significant regional differences in microglial phenotype are present in adults. We found that microglial density peaks in the ventral tegmental area (VTA) and nucleus accumbens (NAc) during the third postnatal week, driven by a burst of microglial proliferation. Microglial abundance is then refined to adult levels through a combination of tissue expansion and microglial programmed cell death. This overproduction and refinement of microglia was significantly more pronounced in the NAc than in the VTA and was accompanied by a sharp peak in NAc microglial lysosome abundance in the third postnatal week. Collectively, these data identify a key developmental window when elevated microglial density in discrete basal ganglia nuclei may support circuit refinement and could increase susceptibility to inflammatory insults.

Magnitude and timing of major white matter tract maturation from infancy through adolescence with NODDI

White matter maturation is a nonlinear and heterogeneous phenomenon characterized by axonal packing, increased axon caliber, and a prolonged period of myelination. While current in vivo diffusion MRI (dMRI) methods, like diffusion tensor imaging (DTI), have successfully characterized the gross structure of major white matter tracts, these measures lack the specificity required to unravel the distinct processes that contribute to microstructural development. Neurite orientation dispersion and density imaging (NODDI) is a dMRI approach that probes tissue compartments and provides biologically meaningful measures that quantify neurite density index (NDI) and orientation dispersion index (ODI). The purpose of this study was to characterize the magnitude and timing of major white matter tract maturation with NODDI from infancy through adolescence in a cross-sectional cohort of 104 subjects (0.6–18.8 years). To probe the regional nature of white matter development, we use an along-tract approach that partitions tracts to enable more fine-grained analysis. Major white matter tracts showed exponential age-related changes in NDI with distinct maturational patterns. Overall, analyses revealed callosal fibers developed before association fibers. Our along-tract analyses elucidate spatially varying patterns of maturation with NDI that are distinct from those obtained with DTI. ODI was not significantly associated with age in the majority of tracts. Our results support the conclusion that white matter tract maturation is heterochronous process and, furthermore, we demonstrate regional variability in the developmental timing within major white matter tracts. Together, these results help to disentangle the distinct processes that contribute to and more specifically define the time course of white matter maturation.

The spatio-temporal dynamics of mitochondrial membrane potential during oocyte maturation.

Mitochondria are highly dynamic organelles and their distribution, structure and activity affect a wide range of cellular functions. Mitochondrial membrane potential (∆Ψm) is an indicator of mitochondrial activity and plays a major role in ATP production, redox balance, signaling and metabolism. Despite the absolute reliance of oocyte and early embryo development on mitochondrial function, there is little known about the spatial and temporal aspects of ΔΨm during oocyte maturation. The one exception is that previous findings using a ΔΨm indicator, JC-1, report that mitochondria in the cortex show a preferentially increased ΔΨm, relative to the rest of the cytoplasm. Using live-cell imaging and a new ratiometric approach for measuring ΔΨm in mouse oocytes, we find that ΔΨm increases through the time course of oocyte maturation and that mitochondria in the vicinity of the first meiotic spindle show an increase in ΔΨm, compared to other regions of the cytoplasm. We find no evidence for an elevated ΔΨm in the oocyte cortex. These findings suggest that mitochondrial activity is adaptive and responsive to the events of oocyte maturation at both a global and local level. In conclusion, we have provided a new approach to reliably measure ΔΨm that has shed new light onto the spatio-temporal regulation of mitochondrial function in oocytes and early embryos.

Delayed maturation of GABAergic signaling in the Scn1a and Scn1b mouse models of Dravet Syndrome

Dravet syndrome (DS) is a catastrophic developmental and epileptic encephalopathy characterized by severe, pharmacoresistant seizures and the highest risk of Sudden Unexpected Death in Epilepsy (SUDEP) of all epilepsy syndromes. Here, we investigated the time course of maturation of neuronal GABAergic signaling in the Scn1b−/− and Scn1a+/− mouse models of DS. We found that GABAergic signaling remains immature in both DS models, with a depolarized reversal potential for GABAA-evoked currents compared to wildtype in the third postnatal week. Treatment of Scn1b−/− mice with bumetanide resulted in a delay in SUDEP onset compared to controls in a subset of mice, without prevention of seizure activity or amelioration of failure to thrive. We propose that delayed maturation of GABAergic signaling may contribute to epileptogenesis in SCN1B- and SCN1A-linked DS. Thus, targeting the polarity of GABAergic signaling in brain may be an effective therapeutic strategy to reduce SUDEP risk in DS.

P75 Neurotrophin Receptor Activation Regulates the Timing of the Maturation of Cortical Parvalbumin Interneuron Connectivity and Promotes Juvenile-like Plasticity in Adult Visual Cortex.

By virtue of their extensive axonal arborization and perisomatic synaptic targeting, cortical inhibitory parvalbumin (PV) cells strongly regulate principal cell output and plasticity and modulate experience-dependent refinement of cortical circuits during development. An interesting aspect of PV cell connectivity is its prolonged maturation time course, which is completed only by end of adolescence. The p75 neurotrophin receptor (p75NTR) regulates numerous cellular functions; however, its role on cortical circuit development and plasticity remains elusive, mainly because localizing p75NTR expression with cellular and temporal resolution has been challenging. By using RNAscope and a modified version of the proximity ligation assay, we found that p75NTR expression in PV cells decreases between the second and fourth postnatal week, at a time when PV cell synapse numbers increase dramatically. Conditional knockout of p75NTR in single PV neurons in vitro and in PV cell networks in vivo causes precocious formation of PV cell perisomatic innervation and perineural nets around PV cell somata, therefore suggesting that p75NTR expression modulates the timing of maturation of PV cell connectivity in the adolescent cortex. Remarkably, we found that PV cells still express p75NTR in adult mouse cortex of both sexes and that its activation is sufficient to destabilize PV cell connectivity and to restore cortical plasticity following monocular deprivation in vivo Together, our results show that p75NTR activation dynamically regulates PV cell connectivity, and represent a novel tool to foster brain plasticity in adults.SIGNIFICANCE STATEMENT In the cortex, inhibitory, GABA-releasing neurons control the output and plasticity of excitatory neurons. Within this diverse group, parvalbumin-expressing (PV) cells form the larger inhibitory system. PV cell connectivity develops slowly, reaching maturity only at the end of adolescence; however, the mechanisms controlling the timing of its maturation are not well understood. We discovered that the expression of the neurotrophin receptor p75NTR in PV cells inhibits the maturation of their connectivity in a cell-autonomous fashion, both in vitro and in vivo, and that p75NTR activation in adult PV cells promotes their remodeling and restores cortical plasticity. These results reveal a new p75NTR function in the regulation of the time course of PV cell maturation and in limiting cortical plasticity.

Early postnatal development of pyramidal neurons across layers of the mouse medial prefrontal cortex

Mammalian neocortex is a highly layered structure. Each layer is populated by distinct subtypes of principal cells that are born at different times during development. While the differences between principal cells across layers have been extensively studied, it is not known how the developmental profiles of neurons in different layers compare. Here, we provide a detailed morphological and functional characterisation of pyramidal neurons in mouse mPFC during the first postnatal month, corresponding to known critical periods for synapse and neuron formation in mouse sensory neocortex. Our data demonstrate similar maturation profiles of dendritic morphology and intrinsic properties of pyramidal neurons in both deep and superficial layers. In contrast, the balance of synaptic excitation and inhibition differs in a layer-specific pattern from one to four postnatal weeks of age. Our characterisation of the early development and maturation of pyramidal neurons in mouse mPFC not only demonstrates a comparable time course of postnatal maturation to that in other neocortical circuits, but also implies that consideration of layer- and time-specific changes in pyramidal neurons may be relevant for studies in mouse models of neuropsychiatric and neurodevelopmental disorders.

Inhibition of Semaphorin3A Promotes Ocular Dominance Plasticity in the Adult Rat Visual Cortex.

Perineuronal nets (PNNs) are condensed structures in the extracellular matrix that mainly surround GABA-ergic parvalbumin-positive interneurons in the adult brain. Previous studies revealed a parallel between PNN formation and the closure of the critical period. Moreover, ocular dominance plasticity is enhanced in response to PNN manipulations in adult animals. However, the mechanisms through which perineuronal nets modulate plasticity are still poorly understood. Recent work indicated that perineuronal nets may convey molecular signals by binding and storing proteins with important roles in cellular communication. Here we report that semaphorin3A (Sema3A), a chemorepulsive axon guidance cue known to bind to important perineuronal net components, is necessary to dampen ocular dominance plasticity in adult rats. First, we showed that the accumulation of Sema3A in PNNs in the visual cortex correlates with critical period closure, following the same time course of perineuronal nets maturation. Second, the accumulation of Sema3A in perineuronal nets was significantly reduced by rearing animals in the dark in the absence of any visual experience. Finally, we developed and characterized a tool to interfere with Sema3A signaling by means of AAV-mediated expression of receptor bodies, soluble proteins formed by the extracellular domain of the endogenous Sema3A receptor (neuropilin1) fused to a human IgG Fc fragment. By using this tool to antagonize Sema3A signaling in the adult rat visual cortex, we found that the specific inhibition of Sema3A promoted ocular dominance plasticity. Thus, Sema3A accumulates in perineuronal nets in an experience-dependent manner and its presence in the mature visual cortex inhibits plasticity.

The Expression Profile of Connexin-30 and Connexin-32 in the Somatosensory and Visual Cortex of Rats during Early Postnatal Ontogeny

Many studies are focused on the mechanisms of CNS formation, especially on the molecular bases of CNS functioning at different stages of maturation. It is known that functional maturation of different parts of the neocortex occurs at different time points of postnatal ontogeny and gap junctions play an important role in this process. So far, it was not clear whether the expression of major proteins that form gap junctions, connexins, is uniform in the neocortex during its maturation. We compared the dynamics of mRNA level of connexin-30 (Cx30, gjb6) and connexin-32 (Cx32, gjb1) in the somatosensory and visual parts of the neocortex during period of early postnatal ontogeny. We measured the mRNA level of mentioned connexins using quantitative real-time PCR after reverse transcription in the samples of neocortex collected at postnatal days 5, 8, 10, 13, and 20. We found that the level of Cx30 mRNA progressively increased in the somatosensory neocortex from the 5th to 20th day of postnatal ontogeny. In contrast, the level of Cx30 mRNA in the visual cortex began to increase only after the 10th day of postnatal development. Analysis of Cx32 expression showed that its expression started to increase only after 10th day in the somatosensory cortex and after 13th day in the visual cortex. Taken together, our data suggest that the expression of Cx30 and Cx32 is more intense in the somatosensory than in the visual neocortex at early stages of ontogeny which may reflect different time course of maturation of these neocortical areas.

Effects of Strain and Species on the Septo-Temporal Distribution of Adult Neurogenesis in Rodents.

The functional septo-temporal (dorso-ventral) differentiation of the hippocampus is accompanied by gradients of adult hippocampal neurogenesis (AHN) in laboratory rodents. An extensive septal AHN in laboratory mice suggests an emphasis on a relation of AHN to tasks that also depend on the septal hippocampus. Domestication experiments indicate that AHN dynamics along the longitudinal axis are subject to selective pressure, questioning if the septal emphasis of AHN in laboratory mice is a rule applying to rodents in general. In this study, we used C57BL/6 and DBA2/Crl mice, wild-derived F1 house mice and wild-captured wood mice and bank voles to look for evidence of strain and species specific septo-temporal differences in AHN. We confirmed the septal > temporal gradient in C57BL/6 mice, but in the wild species, AHN was low septally and high temporally. Emphasis on the temporal hippocampus was particularly strong for doublecortin positive (DCX+) young neurons and more pronounced in bank voles than in wood mice. The temporal shift was stronger in female wood mice than in males, while we did not see sex differences in bank voles. AHN was overall low in DBA and F1 house mice, but they exhibited the same inversed gradient as wood mice and bank voles. DCX+ young neurons were usually confined to the subgranular zone and deep granule cell layer. This pattern was seen in all animals in the septal and intermediate dentate gyrus. In bank voles and wood mice however, the majority of temporal DCX+ cells were radially dispersed throughout the granule cell layer. Some but not all of the septo-temporal differences were accompanied by changes in the DCX+/Ki67+ cell ratios, suggesting that new neuron numbers can be regulated by both proliferation or the time course of maturation and survival of young neurons. Some of the septo-temporal differences we observe have also been found in laboratory rodents after the experimental manipulation of the molecular mechanisms that control AHN. Adaptations of AHN under natural conditions may operate on these or similar mechanisms, adjusting neurogenesis to the requirements of hippocampal function.

Differential Postnatal Expression of Neuronal Maturation Markers in the Dentate Gyrus of Mice and Rats.

The dentate gyrus (DG) is a unique structure of the hippocampus that is distinguished by ongoing neurogenesis throughout the lifetime of an organism. The development of the DG, which begins during late gestation and continues during the postnatal period, comprises the structural formation of the DG as well as the establishment of the adult neurogenic niche in the subgranular zone (SGZ). We investigated the time course of postnatal maturation of the DG in male C57BL/6J mice and male Sprague-Dawley rats based on the distribution patterns of the immature neuronal marker doublecortin (DCX) and a marker for mature neurons, calbindin (CB). Our findings demonstrate that the postnatal DG is marked by a substantial maturation with a high number of DCX-positive granule cells (GCs) during the first two postnatal weeks followed by a progression toward more mature patterns and increasing numbers of CB-positive GCs within the subsequent 2 weeks. The most substantial shift in maturation of the GC population took place between P7 and P14 in both mice and rats, when young, immature DCX-positive GCs became confined to the innermost part of the GC layer (GCL), indicative of the formation of the SGZ. These results suggest that the first month of postnatal development represents an important transition phase during which DG neurogenesis and the maturation course of the GC population becomes analogous to the process of adult neurogenesis. Therefore, the postnatal DG could serve as an attractive model for studying a growing and functionally maturing neural network. Direct comparisons between mice and rats revealed that the transition from immature DCX-positive to mature CB-positive GCs occurs more rapidly in the rat by approximately 4–6 days. The remarkable species difference in the speed of maturation on the GC population level may have important implications for developmental and neurogenesis research in different rodent species and strains.

Early survival and delayed death of developmentally-born dentate gyrus neurons.

The storage and persistence of memories depends on plasticity in the hippocampus. Adult neurogenesis produces new neurons that mature through critical periods for plasticity and cellular survival, which determine their contributions to learning and memory. However, most granule neurons are generated prior to adulthood; the maturational timecourse of these neurons is poorly understood compared to adult-born neurons but is essential to identify how the dentate gyrus (DG), as a whole, contributes to behavior. To characterize neurons born in the early postnatal period, we labeled DG neurons born on postnatal day 6 (P6) with BrdU and quantified maturation and survival across early (1 hr to 8 weeks old) and late (2-6 months old) cell ages. We find that the dynamics of developmentally-born neuron survival is essentially the opposite of neurons born in adulthood: P6-born neurons did not go through a period of cell death during their immature stages (from 1 to 8 weeks). In contrast, 17% of P6-born neurons died after reaching maturity, between 2 and 6 months of age. Delayed death was evident from the loss of BrdU+ cells as well as pyknotic BrdU+ caspase3+ neurons within the superficial granule cell layer. Patterns of DCX, NeuN, and activity-dependent Fos expression indicate that developmentally-born neurons mature over several weeks and a sharp peak in zif268 expression at 2 weeks suggests that developmentally-born neurons mature faster than adult-born neurons (which peak at 3 weeks). Collectively, our findings are relevant for understanding how developmentally-born DG neurons contribute to memory and disorders throughout the lifespan. High levels of early survival and zif268 expression may promote learning, while also rendering neurons sensitive to insults at defined stages. Late neuronal death in young adulthood may result in the loss of hundreds of thousands of DG neurons, which could impact memory persistence and contribute to hippocampal/DG atrophy in disorders such as depression.