Selenoproteins in Nervous System Development and Function

Selenoproteins are a distinct class of proteins that are characterized by the co-translational incorporation of selenium (Se) in the form of the 21st amino acid selenocysteine. Selenoproteins provide a key defense against oxidative stress, as many of these proteins participate in oxidation-reduction reactions neutralizing reactive oxygen species, where selenocysteine residues act as catalytic sites. Many selenoproteins are highly expressed in the brain, and mouse knockout studies have determined that several are required for normal brain development. In parallel with these laboratory studies, recent reports of rare human cases with mutations in genes involved in selenoprotein biosynthesis have described individuals with an assortment of neurological problems that mirror those detailed in knockout mice. These deficits include impairments in cognition and motor function, seizures, hearing loss, and altered thyroid metabolism. Additionally, due to the fact that oxidative stress is a key feature of neurodegenerative disease, there is considerable interest in the therapeutic potential of selenium supplementation for human neurological disorders. Studies performed in cell culture and rodent models have demonstrated that selenium administration attenuates oxidative stress, prevents neurodegeneration, and counters cell signaling mechanisms known to be dysregulated in certain disease states. However, there is currently no definitive evidence in support of selenium supplementation to prevent and/or treat common neurological conditions in the general population. It appears likely that, in humans, supplementation with selenium may only benefit certain subpopulations, such as those that are either selenium-deficient or possess genetic variants that affect selenium metabolism.     

Microglia Function in Central Nervous System Development and Plasticity

The nervous system comprises a remarkably diverse and complex network of different cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in the spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS and highlight exciting new work in the field that has identified roles for these cells in CNS development, maintenance, and plasticity.Microglia are one of the most enigmatic and understudied populations in the brain. Until recently, most of what was known about their function has been associated with their rapid and robust responses to disease and injury (Ransohoff and Perry 2009; Graeber 2010; Ransohoff and Cardona 2010). The idea that microglia could be performing normal, homeostatic functions is a relatively new concept, galvanized by pioneering in vivo imaging studies, which revealed that the processes of “resting” microglia are highly motile in the intact, healthy adult brain (Davalos et al. 2005; Nimmerjahn et al. 2005). Remarkably, it is estimated that these microglial processes survey the entire brain parenchyma within a matter of hours, raising many questions about the significance of this immune surveillance system.Since these initial findings, there has been a surge in the field to examine functional roles of microglia in the healthy central nervous system (CNS), with a primary focus on postnatal development. This focus was, to a large extent, incited by a landmark fate-mapping study in the mouse showing that microglia develop from primitive myeloid progenitors in the embryonic yolk sac and begin to colonize the brain during early embryonic development (approximately embryonic day 9.5 [∼E9.5] in the mouse) (Ginhoux et al. 2010). Given this early colonization, microglia are poised to play important roles in shaping the developing CNS and contributing to overall nervous system function. Indeed, recent work has shown that microglia in the developing CNS can physically interact with neuronal soma and synapses in response to changes in neural activity, and data implicate microglia in many functions required to build and wire the developing CNS ranging from neurogenesis to synaptic pruning (Tremblay 2011; Tremblay et al. 2011; Kettenmann et al. 2013; Schafer et al. 2013; Wake et al. 2013; Salter and Beggs 2014). Furthermore, emerging work in the juvenile and adult reveal that these interactions and functions observed in the postnatal brain occur more broadly to affect plasticity over the life span of the animal, ultimately affecting behavior.In this chapter, we review the latest findings in the field on microglia function in CNS development and plasticity. Our goal is to give a comprehensive and critical perspective of this relatively new area of research and highlight new questions. Furthermore, we discuss novel strategies to manipulate microglia function that will contribute to our understanding of these cells in the healthy nervous system and, ultimately, help to identify mechanisms of disease.     

Prenatal Stress and Adaptive Behavior of Offspring: The Role of Placental Serotonin

Doklady Biochemistry and Biophysics - The effect of mild prenatal stress in mice, leading to an increase in the placental serotonin level, on the formation of adaptive behavior in male offspring at...     

Maternal Neurofascin-Specific Autoantibodies Bind to Structures of the Fetal Nervous System during Pregnancy,but Have No Long Term Effect on Development in the Rat

Neurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum. Results: Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody. Conclusions: We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children.     

Prenatal Endotoxemia and Placental Drug Transport in The Mouse: Placental Size-Specific Effects

Lipopolysaccharide (LPS) in high doses inhibits placental multidrug resistance P-glycoprotein (P-gp - Abcb1a/b) and breast cancer resistance protein (BCRP - Abcg2). This potentially impairs fetal protection against harmful factors in the maternal circulation. However, it is unknown whether LPS exposure, at doses that mimic sub-lethal clinical infection, alters placental multidrug resistance. We hypothesized that sub-lethal (fetal) LPS exposure reduces placental P-gp activity. Acute LPS (n = 19;150 µg/kg; ip) or vehicle (n = 19) were given to C57BL/6 mice at E15.5 and E17.5. Placentas and fetal-units were collected 4 and 24 h following injection. Chronic LPS (n = 6; 5 µg/kg/day; ip) or vehicle (n = 5) were administered from E11.5–15.5 and tissues were collected 4 h after final treatment. P-gp activity was assessed by [³H]digoxin accumulation. Placental Abcb1a/b, Abcg2, interleukin-6 (Il-6), Tnf-α, Il-10 and toll-like receptor-4 (Tlr-4) mRNA were measured by qPCR. Maternal plasma IL-6 was determined. At E15.5, maternal IL-6 was elevated 4 h after single (p<0.001) and chronic (p<0.05) LPS, but levels had returned to baseline by 24 h. Placental Il-6 mRNA was also increased after acute and chronic LPS treatments (p<0.05), whereas Abcb1a/b and Abcg2 mRNA were unaffected. However, fetal [³H]digoxin accumulation was increased (p<0.05) 4 h after acute LPS, and maternal [³H]digoxin myocardial accumulation was increased (p<0.05) in mice exposed to chronic LPS treatments. There was a negative correlation between fetal [³H]digoxin accumulation and placental size (p<0.0001). Acute and chronic sub-lethal LPS exposure resulted in a robust inflammatory response in the maternal systemic circulation and placenta. Acute infection decreased placental P-gp activity in a time- and gestational age-dependent manner. Chronic LPS decreased P-gp activity in the maternal myocardium and there was a trend for fetuses with smaller placentas to accumulate more P-gp substrate than their larger counterparts. Collectively, we demonstrate that acute sub-lethal LPS exposure during pregnancy impairs fetal protection against potentially harmful xenobiotics in the maternal circulation.     

BRCA2 Function and the Central Nervous System

Defective responses to DNA double strand breaks (DSBs) in the nervous system can lead to neurodegeneration or tumorigenesis. A key player in the repair of DNA DSBs is the tumor suppressor BRCA2, an essential component of the homologous recombination repair pathway and the Fanconi Anemia complex. We recently demonstrated that BRCA2 was required for normal neurogenesis and prevention of medulloblastoma brain tumors. Here, we discuss how this study contributes both to our understanding of BRCA2 functions in vivo, and the tissue-specific requirements for DNA repair and damage-signaling pathways.     

Prenatal Stress Down-Regulates Reelin Expression by Methylation of Its Promoter and Induces Adult Behavioral Impairments in Rats

Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination and synaptic maturation, and its deregulation has been associated with maladaptive conditions. In the present study, we address the effect of prenatal restraint stress (PNS) upon Reelin expression and signaling in pregnant rats during the last 10 days of pregnancy. Animals from one group, including control and PNS exposed fetuses, were sacrificed and analyzed using immunohistochemical, biochemical, cell biology and molecular biology approaches. We scored changes in the expression of Reelin, its signaling pathway and in the methylation of its promoter. A second group included control and PNS exposed animals maintained until young adulthood for behavioral studies. Using the optical dissector, we show decreased numbers of Reelin-positive neurons in cortical layer I of PNS exposed animals. In addition, neurons from PNS exposed animals display decreased Reelin expression that is paralleled by changes in components of the Reelin-signaling cascade, both in vivo and in vitro. Furthermore, PNS induced changes in the DNA methylation levels of the Reelin promoter in culture and in histological samples. PNS adult rats display excessive spontaneous locomotor activity, high anxiety levels and problems of learning and memory consolidation. No significant visuo-spatial memory impairment was detected on the Morris water maze. These results highlight the effects of prenatal stress on the Cajal-Retzius neuronal population, and the persistence of behavioral consequences using this treatment in adults, thereby supporting a relevant role of PNS in the genesis of neuropsychiatric diseases. We also propose an in vitro model that can yield new insights on the molecular mechanisms behind the effects of prenatal stress.     

Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight

Background

It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population–based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age.

Methodology/Principal Findings

We followed 65,212 children born in Denmark from 1970–1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08–2.61) at 12 years of age and 1.63 (95% CI 1.00–2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71–6.42 at age 12, and OR 2.31, 95% CI 1.08–4.97 at age 13).

Conclusions/Significance

Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.     

Peripheral Nervous System Neuropathology and Progressive Sensory Impairments in a Mouse Model of Mucopolysaccharidosis IIIB

The lysosomal storage pathology in Mucopolysaccharidosis (MPS) IIIB manifests in cells of virtually all organs. However, it is the profound role of the neurological pathology that leads to morbidity and mortality in this disease, and has been the major challenge to developing therapies. To date, MPS IIIB neuropathologic and therapeutic studies have focused predominantly on changes in the central nervous system (CNS), especially in the brain, and little is known about the disease pathology in the peripheral nervous system (PNS). This study demonstrates characteristic lysosomal storage pathology in dorsal root ganglia affecting neurons, satellite cells (glia) and Schwann cells. Lysosomal storage lesions were also observed in the myoenteric plexus and submucosal plexus, involving enteric neurons with enteric glial activation. Further, MPS IIIB mice developed progressive impairments in sensory functions, with significantly reduced response to pain stimulation that became detectable at 4–5 months of age as the disease progressed. These data demonstrate that MPS IIIB neuropathology manifests not only in the entire CNS but also the PNS, likely affecting both afferent and efferent neural signal transduction. This study also suggests that therapeutic development for MPS IIIB may benefit from targeting the entire nervous system.     

Central Nervous System PET-CT Imaging Reveals Regional Impairments in Pediatric Patients with Wolfram Syndrome

Wolfram syndrome (WFS) is inherited as an autosomal recessive disease with main clinical features of diabetes mellitus, optic atrophy, diabetes insipidus and deafness. However, various neurological defects may also be detected. The aim of this study was to evaluate aspects of brain structure and function using PET-CT (positron emission tomography and computed tomography) and MRI (magnetic resonance imaging) in pediatric patients with WFS. Regional changes in brain glucose metabolism were measured using standardized uptake values (SUVs) based on images of (¹⁸F) fluorodeoxyglucose (FDG) uptake in 7 WFS patients aged 10.1–16.0 years (mean 12.9±2.4) and in 20 healthy children aged 3–17.9 years (mean 12.8±4.1). In all patients the diagnosis of WFS was confirmed by DNA sequencing of the WFS1 gene. Hierarchical clustering showed remarkable similarities of glucose uptake patterns among WFS patients and their differences from the control group. SUV data were subsequently standardized for age groups <13 years old and>13 years old to account for developmental differences. Reduced SUVs in WFS patients as compared to the control group for the bilateral brain regions such as occipital lobe (−1.24±1.20 vs. −0.13±1.05; p = 0.028) and cerebellum (−1.11±0.69 vs. −0.204±1.00; p = 0.036) were observed and the same tendency for cingulate (−1.13±1.05 vs. −0.15±1.12; p = 0.056), temporal lobe (−1.10±0.98 vs. −0.15±1.10; p = 0.057), parietal lobe (−1.06±1.20 vs. −0.08±1.08; p = 0.058), central region (−1.01±1.04 vs. −0.09±1.06; p = 0.060), basal ganglia (−1.05±0.74 vs. −0.20±1.07; p = 0.066) and mesial temporal lobe (−1.06±0.82 vs. −0.26±1.08; p = 0.087) was also noticed. After adjusting for multiple hypothesis testing, the differences in glucose uptake were non-significant. For the first time, regional differences in brain glucose metabolism among patients with WFS were shown using PET-CT imaging.     

TRPV1通道在中枢神经系统中的功能

TRPV1（transient receptor potential vanilloid 1）是在机体广泛分布的非选择性阳离子通道,能被氢离子、高温以及其它内源性和外源性配体激活.其在外周神经系统中主要参与伤害性高温的感受以及痛觉过敏等生理机制.TRPV1在中枢神经系统中功能的研究进展主要体现在突触传递,体温调节,痛觉的调制和细胞凋亡等方面.TRPV1的激活降低突触前谷氨酸的释放及增强已存在的突触后AMPA受体的作用,从而增强了突触传递效能.外周的TRPV1通过激活能够抑制血管的收缩和生热作用,从而抑制体温的升高,当TRPV1被阻断时就发生体温过高,而TRPV1体温调节的中枢作用机制可能是通过直接作用于体温调节中枢.脑干的痛觉调制环路的激活TRPV1可以引起谷氨酸盐的释放,进而激活突触后I类mGlu受体以及NMDA受体,从而起到镇痛的功能.另外近年发现TRPV1在中枢也参与呕吐、呼吸、心率及血压的调节.     

The Role of Oxidative Stress in Nervous System Aging

While oxidative stress is implicated in aging, the impact of oxidative stress on aging in the peripheral nervous system is not well understood. To determine a potential mechanism for age-related deficits in the peripheral nervous system, we examined both functional and morphological changes and utilized microarray technology to compare normal aging in wild-type mice to effects in copper/zinc superoxide dismutase-deficient (Sod1^−/−) mice, a mouse model of increased oxidative stress. Sod1^−/− mice exhibit a peripheral neuropathy phenotype with normal sensory nerve function and deficits in motor nerve function. Our data indicate that a decrease in the synthesis of cholesterol, which is vital to myelin formation, correlates with the structural deficits in axons, myelin, and the cell body of motor neurons in the Sod1^+/+ mice at 30 months and the Sod1^−/− mice at 20 months compared with mice at 2 months. Collectively, we have demonstrated that the functional and morphological changes within the peripheral nervous system in our model of increased oxidative stress are manifested earlier and resemble the deficits observed during normal aging.     

Age-Dependent Effects of Prenatal Stress on the Corticolimbic Dopaminergic System Development in the Rat Male Offspring

We have previously demonstrated that prenatal stress (PS) exerts an impairment of midbrain dopaminergic (DA) system metabolism especially after puberty, suggesting a particular sensitivity of DA development to variations in gonadal hormonal peaks. Furthermore we demonstrated that PS alters the long term androgens profile of the rat male offspring from prepubertal to adult stages. In this work we evaluated the sexual hormones activational effects on the DA system by analysing PS effects on the dopaminergic D2-like (D2R) and on the gonadal hormones receptor levels on cortical and hippocampal areas of prepubertal and adult male offspring. We further evaluated the dendritic arborization in the same areas by quantifying MAP2 immunoexpresion. Our results show that PS affected oestrogen receptor alpha (ERα) expression: mRNA er1s and ERα protein levels were decreased on prefrontal cortex and hippocampus of adult offspring. Moreover, PS reduced D2R protein levels in hippocampus of prepubertal rats. Morphological studies revealed that prepubertal PS rats presented decreased MAP2 immunoexpression in both areas suggesting that PS reduces the number of dendritic arborizations. Our findings suggest that PS exerts long-term effects on the DA system by altering the normal connectivity in the areas, and by modulating the expression of D2R and ERα in an age-related pattern. Since the developing forebrain DA system was shown to be influenced by androgen exposure, and PS was shown to disrupt perinatal testosterone surges, our results suggest that prenatal insults might be affecting the organizational role of androgens and differentially modulating their activational role on the DA development.     

Function of Catecholamine-containing Neurones in Mammalian Central Nervous System

SEVERAL chemical substances are involved in synaptic transmission in the mammalian central nervous system^1–3. The Falck-Hillarp technique⁴ has demonstrated noradrenaline, dopamine and 5-hydroxytryptamine within nerve cell bodies and terminals^5,6 and the belief that these amines act as neurohumours is strengthened by observations that nerve fibre activation leads to their release from the terminals^7,8. Histo-chemical evidence suggests that discrete systems of neurones can be identified by their content of particular amines and it seems possible that such neurohumorally homogeneous systems have a functional as well as a chemical identity. Before the anatomical distribution of amine-containing neurones had been described, Brodie and Shore⁹ proposed that noradrenaline functions as the central neurohumour of the sympathetic and 5-hydroxytryptamine of the parasympathetic system. This suggestion has not been supported by anatomical evidence; the amine-containing neurones form systems of small diameter fibres of very diffuse terminal distribution, which do not correspond to recognized ascending or descending pathways^5,6, although amine-containing neurones in invertebrates have been identified as sensory systems¹⁰.     

Normal and Atypical Butyrylcholinesterases in Placental Development, Function, and Malfunction

1. In utero exposure to poisons and drugs (e.g., anticholinesterases, cocaine) is frequently associated with spontaneous abortion and placental malfunction. The major protein interacting with these compounds is butyrylcholinesterase (BuChE), which attenuates the effects of such xenobiotics by their hydrolysis or sequestration. Therefore, we studied BuChE expression during placental development.2. RT-PCR revealed both BuChEmRNA and acetylcholinesterase (AChE) mRNA throughout gestation. However, cytochemical staining detected primarily BuChE activity in first-trimester placenta but AChE activity in term placenta.3. As the atypical variant of BuChE has a narrower specificity for substrates and inhibitors than the normal enzyme, we investigated its interactions with -solanine and cocaine, and sought a correlation between the occurrence of this variant and placental malfunction.4. Atypical BuChE of serum or recombinant origin presented >10-fold weaker affinities than normal BuChE for cocaine and -solanine. However, BuChE in the serum of a heterozygote and a homozygous normal were similar in their drug affinities. Therefore, heterozygous serum or placenta can protect the fetus from drug or poison exposure, unlike homozygous atypical serum or placenta.5. Genotype analyses revealed that heterozygous carriers of atypical BuChE were threefold less frequent among 49 patients with placental malfunction than among 76 controls or the entire Israeli population. These observations exclude heterozygote carriers of atypical BuChE from being at high risk for placental malfunction under exposure to anticholinesterases.     

Formation of Coordinational Function of the Central Nervous System: Phylo- and Ontogenetic Aspects

A comparative-ontogenetic analysis has been performed of literature and authors' own data obtained in studies on regularities of formation of interrelations of somatic-autonomic reactions in the process of phylo- and ontogenetic development in the row of vertebrates. This analysis has allowed showing universality in formation of the motor-cardiac reflex both in phylo- and in ontogenesis on the basis of maturation of these reactions and the coordinational function of the nervous system in the process of phylogenesis (fish, amphibians) and prenatal ontogenesis of mammals (human fetuses). This indicates the common character of embryonal and neuronal mechanisms of the autorhythmical nature both in phylo- and in ontogenesis of vertebrates.     

Gender Differences in the Effects of Prenatal Stress on Brain Development and Behaviour

An increased incidence of anxiety, depression and attention deficits in children has been linked to psychological stress during pregnancy. Subjection of a pregnant rat to stress at a time when the foetal limbic and hypothalamic pituitary adrenal (HPA) axes develop results in anxiogenic and depressive behaviour and learning and attention deficits in the offspring, which depend on its gender, intensity and timing of the maternal stress and behaviour being tested. Maternal stress increases corticosterone levels in the foetal brain, decreases foetal testosterone and brain aromatase activity in males, and alters brain catecholamine activity to that in females. Learning deficits, reductions in hippocampal neurogenesis, LTP and dendritic spine density in the prefrontal cortex are more readily seen in prenatally-stressed males, while anxiety, depression and increased response of the HPA axis to stress are more prevalent in females. Genders may differ in the sensitivity of developing brain areas to stress hormones. Special issue dedicated to Dr. Moussa Youdim.     

Prenatal Nicotine and Maternal Deprivation Stress De-Regulate the Development of CA1, CA3, and Dentate Gyrus Neurons in Hippocampus of Infant Rats

Adverse experiences by the developing fetus and in early childhood are associated with profound effects on learning, emotional behavior, and cognition as a whole. In this study we investigated the effects of prenatal nicotine exposure (NIC), postnatal maternal deprivation (MD) or the combination of the two (NIC+MD) to determine if hippocampal neuron development is modulated by exposure to drugs of abuse and/or stress. Growth of rat offspring exposed to MD alone or NIC+MD was repressed until after weaning. In CA1 but not CA3 of postnatal day 14 (P14) pups, MD increased pyramidal neurons, however, in dentate gyrus (DG), decreased granule neurons. NIC had no effect on neuron number in CA1, CA3 or DG. Unexpectedly, NIC plus MD combined caused a synergistic increase in the number of CA1 or CA3 neurons. Neuron density in CA regions was unaffected by treatment, but in the DG, granule neurons had a looser packing density after NIC, MD or NIC+MD exposure. When septotemporal axes were analyzed, the synergism of stress and drug exposure in CA1 and CA3 was associated with rostral, whereas MD effects were predominantly associated with caudal neurons. TUNEL labeling suggests no active apoptosis at P14, and doublecortin positive neurons and mossy fibers were diminished in NIC+MD relative to controls. The laterality of the effect of nicotine and/or maternal deprivation in right versus left hippocampus was also analyzed and found to be insiginificant. We report for the first time that early life stressors such as postnatal MD and prenatal NIC exposure, when combined, may exhibit synergistic consequences for CA1 and CA3 pyramidal neuron development, and a potential antagonistic influence on developing DG neurons. These results suggest that early stressors may modulate neurogenesis, apoptosis, or maturation of glutamatergic neurons in the hippocampus in a region-specific manner during critical periods of neurodevelopment.