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PubMed2005

Postoperative lactate concentrations predict the outcome of infants aged 6 weeks or less after intracardiac surgery: a cohort follow-up to 18 months.

OBJECTIVES: An observational cohort study was conducted in infants less than 6 weeks of age undergoing intracardiac surgery to examine the predictive value of serial postoperative lactate determination on survival and early childhood neurodevelopment. METHODS: A total of 85 infants with congenital heart disease underwent intracardiac surgery between 1996 and 1999. Differences in serial lactate concentrations after surgery among 3 outcome groups were compared. The predictive value of plasma lactate concentration on outcome (1) at discharge from initial hospitalization and (2) 18 to 24 months postnatal age was examined. RESULTS: Compared with survivors, the nonsurvivors had higher lactate concentrations on admission to the pediatric intensive care unit at day 1 peak and area under the curve of the lactate profile than those of adverse and intact survivors (all P < .001, analysis of variance). Significant differences in the time for lactate concentrations to return to 2 mmol/L or less during the first postoperative day were observed among the groups: nonsurvivors > adverse survivors > intact survivors. Lactate concentrations of less than 7 mmol/L on admission or less than 8 mmol/L at day 1 peak predicted survival with 82% sensitivity and 83% specificity, and positive and negative predictive values of 97% and 43%, respectively (P < .001, chi2). Plasma lactate concentrations were associated with adverse outcome but had lower predictive values compared with that for nonsurvival. CONCLUSIONS: Serial lactate determination accurately predicts survival and may help differentiate survivors with adverse outcome from those with intact neurodevelopment in early childhood.

Biomarkers↗

PubMed2005

A summary of recent findings on birth outcomes and developmental effects of prenatal ETS, PAH, and pesticide exposures.

Inner-city minority populations are high-risk groups for adverse birth outcomes and also more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene B[a]P, other ambient polycyclic aromatic hydrocarbons (global PAHs), and residential pesticides. The Columbia Center for Children's Environmental Health (CCCEH) is conducting a prospective cohort study of 700 northern Manhattan pregnant women and newborns to examine the effects of prenatal exposure to these common toxicants on fetal growth, early neurodevelopment, and respiratory health. This paper summarizes results of three published studies demonstrating the effects of prenatal ETS, PAH, and pesticides on birth outcomes and/or neurocognitive development [Perera FP, Rauh V, Whyatt RM, Tsai WY, Bernert JT, Tu YH, et al. Molecular evidence of an interaction between prenatal environment exposures on birth outcomes in a multiethnic population. Environ Health Perspect 2004;12:630-62; Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 2004;26:373-85; Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, et al. Prenatal insecticide exposures, birth weight and length among an urban minority cohort. Environ Health Perspect, in press]. To evaluate the effects of prenatal exposure to ETS, PAHs, and pesticides, researchers analyzed questionnaire data, cord blood plasma (including biomarkers of ETS and pesticide exposure), and B[a]P-DNA adducts (a molecular dosimeter of PAHs). Self-reported ETS was associated with decreased head circumference (P = 0.04), and there was a significant interaction between ETS and adducts such that combined exposure had a significant multiplicative effect on birth weight (P = 0.04) and head circumference (P = 0.01) after adjusting for confounders. A second analysis examined the neurotoxic effects of prenatal ETS exposure and postpartum material hardship (unmet basic needs in the areas of food, housing, and clothing) on 2-year cognitive development. Both exposures depressed cognitive development (P < 0.05), and there was a significant interaction such that children with exposure to both ETS and material hardship exhibited the greatest cognitive deficit (7.1 points). A third analysis found that cord chlorpyrifos, and a combined measure of cord chlorpyrifos, diazinon, and propoxur-metabolite, were inversely associated with birth weight and/or length (P < 0.05). These results underscore the importance of policies that reduce exposure to ETS, air pollution, and pesticides with potentially adverse effects on fetal growth and child neurodevelopment.

Child↗

PubMed2004

Age dependence of organophosphate and carbamate neurotoxicity in the postnatal rat: extrapolation to the human.

One important aspect of risk assessment for the organophosphate and carbamate pesticides is to determine whether their neurotoxicity occurs at lower dose levels in human infants compared to adults. Because these compounds probably exert their neurotoxic effects through the inhibition of acetylcholinesterase (AChE), the above question can be narrowed to whether the cholinesterase inhibition and neurotoxicity they produce is age-dependent, both in terms of the effects produced and potency. The rat is the animal model system most commonly used to address these issues. This paper first discusses the adequacy of the postnatal rat to serve as a model for neurodevelopment in the postnatal human, concluding that the two species share numerous pathways of postnatal neurodevelopment, and that the rat in the third postnatal week is the neurodevelopmental equivalent of the newborn human. Then, studies are discussed in which young and adult rats were dosed by identical routes with organophosphates or carbamates. Four pesticides were tested in rat pups in their third postnatal week: aldicarb, chlorpyrifos, malathion, and methamidophos. The first three, but not methamidophos, caused neurotoxicity at dose levels that ranged from 1.8- to 5.1-fold lower (mean 2.6-fold lower) in the 2- to 3-week-old rat compared to the adult. This estimate in the rat, based on a limited data set of three organophosphates and a single carbamate, probably represents the minimum difference in the neurotoxicity of an untested cholinesterase-inhibiting pesticide that should be expected between the human neonate and adult. For the organophosphates, the greater sensitivity of postnatal rats, and, by analogy, that expected for human neonates, is correlated with generally lower levels of the enzymes involved in organophosphate deactivation.

Age Factors↗

PubMed2003

Abnormal cerebral asymmetry and schizophrenia in a subject with Klinefelter's syndrome (XXY).

BACKGROUND: A high incidence of schizophrenia has been reported in individuals with sex chromosome aneuploides (SCAs), and extra-X aneuploidy appears to adversely affect neurodevelopment. We previously examined neurodevelopment in SCA subjects with structural magnetic resonance imaging (MRI) of the brain. We present an XXY subject who subsequently developed schizophrenia. Further examination of the MRI data was undertaken. METHODS: Graphs of MRI-determined regional brain to whole brain volume proportions and cerebral asymmetry indexes were generated for Klinefelter (n = 10) and male control subjects (n = 25) to allow inter-individual comparisons. RESULTS: The index case had reversed prefrontal and temporal lobe asymmetries, and these findings were more marked than in any other subject. CONCLUSIONS: It has been suggested that a genetic locus for schizophrenia may be found on the X chromosome and that the gene(s) concerned are implicated in the development of normal cerebral asymmetries. This case supports these arguments.

Adolescent↗

PubMed2000

Neurosteroid modulation of embryonic neuronal survival in vitro following anoxia.

Neurosteroids are synthesized de novo in the brain from cholesterol or peripheral steroid precursors and modulate inhibitory gamma-aminobutyric acid (GABA(A)) and excitatory N-methyl-D-aspartate (NMDA) receptors. Evidence indicates that neurosteroids are neuroprotective and important during neurodevelopment. We tested the hypothesis that neurosteroids increase embryonic neuronal survival following anoxia in rat embryonic day 18 cerebral cortical cultures to examine potential neurosteroid modulation of this insult during early development. Twenty-four hours after plating in serum-free medium, cultures were exposed to DHEA, DHEAS, or allopregnanolone (10(-10), 10(-8), or 10(-6) M), or vehicle, for 24 h (n=9 per treatment condition). Cultures were then subjected to anoxia for 2 h and subsequently reincubated for 24 h prior to neuron immunostaining with microtubule-associated protein 2 (MAP-2) antibody. Supernatant from DHEA and DHEAS-exposed cultures was tested for 17beta-estradiol metabolite formation by radioimmunoassay. DHEA 10(-6) and 10(-8) M significantly increased neuron survival by 85-87% following anoxia. DHEAS 10(-6) M significantly increased neuron survival by 74% following anoxia, but DHEAS 10(-10) M decreased neuron survival after this insult. Allopregnanolone had modest effects on neuron survival that did not attain statistical significance. 17beta-Estradiol concentrations were below the limit of detection in all specimens tested (sensitivity 4.7 nM). Our data indicate that pretreatment with DHEA and DHEAS at physiologically relevant concentrations promotes neuronal survival following anoxia in embryonic rat cerebral cortical cultures, and that these effects are not secondary to 17beta-estradiol metabolite formation. DHEA and DHEAS modulation of anoxia in embryonic neurons may be relevant to disorders of neurodevelopment involving this insult.

Animals↗

PubMed1994

Long-term developmental follow-up of infants of diabetic mothers.

The neurodevelopmental consequences of maternal insulin-dependent diabetes were studied in 109 infants of diabetic mothers and 90 control infants. The infants born to diabetic mothers included 70 "early entry" subjects and 39 "late entry" subjects. Maternal diabetes control during pregnancy was significantly better in "early entry" mothers than in late-entry mothers, as determined by glycosylated hemoglobin levels. Infants were examined by a psychologist and a developmental pediatrician unaware of group status at 6, 12, 24, and 36 months of age; 71% of the subjects completed the 3-year-study. Neurodevelopment of early-entry subjects was similar to that of control subjects, whereas late-entry subjects scored less well on language measures. Mean head size in late-entry subjects was significantly less (p = 0.03) than in either control subjects or early-entry subjects at age 3 years, and correlated negatively with glycosylated hemoglobin levels during all three trimesters. Less optimal intellectual development was associated with reduced head circumference. In addition, the presence of major congenital malformations was associated with reduced developmental performance through age 2 years. Our results indicate that mothers with insulin-dependent diabetes who maintain good control during pregnancy can expect to have infants who are neurodevelopmentally normal; mothers whose diabetes is less well controlled may have infants with less optimal neurodevelopment.

Child Development↗

PubMed2002

Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert.

Schizophrenia is a major psychiatric disorder which is hypothesized to result from abnormal neurodevelopment or neural changes in adulthood and possibly associated with altered gene expression. To search for genes overexpressed in schizophrenia, cDNA library subtractive hybridization experiments between post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were carried out. One of the genes over-expressed in schizophrenia was identified as Nogo (also known as reticulon 4, RTN4, NI 250, or RTN-X), a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The elevated expression of Nogo mRNA in schizophrenia was confirmed by quantitative reverse transcription-polymerase chain reaction studies: 16.5 pg Nogo cDNA/microg total RNA in schizophrenia, and 10.2 pg Nogo cDNA/microg total RNA in controls (n=7; P=0.01, t-test for n<30). To identify possible polymorphisms in this gene, the Nogo nucleotide sequence was determined in a series of schizophrenia and control samples. The Nogo mRNA was found to contain a CAA insert polymorphism in the 3'-untranslated region. The prevalence of individuals homozygous for this CAA insert was significantly higher in schizophrenia compared to controls in genomic DNA samples extracted from post-mortem brain and blood samples: 17/81 or 21% in schizophrenia and 2/61 or 3% in controls (P=0.0022, chi(2)- and Fisher's exact-tests). Because the 3'-untranslated regions of eukaryotic genes are known to regulate gene expression, the increased frequency of the Nogo CAA insert in schizophrenia may contribute to abnormal regulation of Nogo gene expression, and may indicate a role for Nogo in disturbed neurodevelopment in schizophrenia.

3' Untranslated Regions↗

PubMed1997

Sample and probe: a novel approach for identifying development-specific cis-elements of the enkephalin gene.

We have developed a novel 'sample and probe' approach as a means to identifying specific DNA elements of the enkephalin gene that control differentiation of the enkephalinergic phenotype during neurodevelopment. The approach is a systematic spatiotemporal analysis of protein-DNA interactions; soluble nuclear proteins ('samples') prepared from microdissected regions of the developing brain are 'probed' with radiolabeled DNA fragments representing various regulatory regions of the enkephalin gene. The resulting spatiotemporal 'molecular maps', i.e. characteristic patterns of protein-DNA complexes showed DNA regions that harbor potential cis-elements regulating differentiation of the enkephalin phenotype at various stages of neurodevelopment. DNase I footprint analysis of such a DNA region identified a binding site (GACGGGAGATCGCTCGT) which is similar to the motif for a lymphoid-specific, developmentally regulated transcription factor, Ikaros, suggesting that the developing brain expresses Ikaros-like transcription factor(s) in a spatiotemporally defined manner. In summary, our approach offers a unique view into the chronology of coordinated protein-DNA interactions and will greatly facilitate identifying DNA elements and isolating development-specific transcription factors.

Animals↗

PubMed2000

Developmental lead exposure disturbs expression of synaptic neural cell adhesion molecules in herring gull brains.

Neurobehavioral testing of herring gull chicks (Larus argentatus) in both laboratory and field studies indicates that lead exposure during critical periods of development causes neurological deficits that may compromise survival in the wild. Accumulating evidence suggests that lead impairs neurodevelopment, in part, by altering the expression of cell adhesion molecules (CAMs) responsible for the proper formation and maintenance of neural structure and synaptic function. We examined the adhesion molecules NCAM, L1, and N-cadherin in gull brains to determine whether these CAMs are altered by lead exposure and might serve as markers of developmental neurotoxicity. One-day-old chicks were collected from nesting colonies and were laboratory housed. On post-hatching day (PHD) 2, chicks were given 100 mg/kg lead acetate or saline (intraperitoneally). Birds were killed on PHD 34, 44, or 55 (blood-lead levels averaged 27.4, 20.8, and 19.5 microg/dl, respectively). Brains were removed and stored at -70 degrees C until analysis. Expression of CAMs was determined in synaptosomal preparations by Western blotting and the activity of NCAM-associated sialyltransferase (ST) was determined in purified whole brain golgi apparatus. Elevation in synaptosomal polysialylated NCAM expression and a significant increase in golgi ST activity was observed in lead-treated animals at PHD 34. Reductions in synaptosomal N-cadherin were observed at PHD 34 and 44, while L1 expression appeared unaffected by lead at any time-point. By 55 days post-hatching, no differences in N-cadherin expression, polysialylated NCAM expression or NCAM-associated ST activity were seen in lead-treated animals as compared with age-matched control animals. Lead-induced disruption of CAM expression during early neurodevelopment may contribute to behavioral deficits observed in herring gulls in both the laboratory and the field, and may serve as a marker for heavy metal exposure during postnatal development.

Animals↗

PubMed2002

Expression of macrophage colony-stimulating factor and its receptor in microglia activation is linked to teratogen-induced neuronal damage.

Prenatal exposure to teratogen agents is linked to the pathogenesis of neurodevelopment disorders, but the mechanisms leading to the neurodevelopmental disturbance are poorly understood. To elucidate this, an in vitro model of microglial activation induced by neuronal injury has been characterized. In this connection, exposure of primary microglial cells to the conditioned medium from the neuronal damage induced by teratogen, cyclophosphamide, is accompanied by a reactive microgliosis as assessed by reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, lectin histochemistry, double labeling immunohistochemistry and in situ hybridization. Our results showed that reactive microglia were capable of releasing various cytokines such as tumor necrosis factor-alpha, interleukin-1, interleukin-6, transforming growth factor-beta and nitric oxide. Also, we have shown that macrophage colony-stimulating factor (M-CSF) was in fact produced by the reactive microglia. Concomitant to this was the increased expression of M-CSF receptor in these cells following the teratogen-induced neuronal injury. The up-regulation of M-CSF receptor suggests that the cells are capable of responding to self-derived M-CSF in an autocrine fashion. Results with antibody neutralization further suggest that microglial proinflammatory response, as manifested by cytokine expression in culture, is mediated by M-CSF, which acts as a molecular signal that initiates a microglial reaction. We therefore suggest that microglial activation following cyclophosphamide treatment is not only a response to the neuronal damage, but is also a cause of the damage during pathogenesis of neurodevelopment disorders. To this end, the increased expression of M-CSF and its receptor on microglia would be directly linked to the active cell proliferation and proinflammatory response in the teratogen-induced injury.

Animals↗

PubMedDate not supplied

Early environmental stress and biological vulnerability to drug abuse.

It has long been believed that stress and drug abuse are related. Studies using animal models have repeatedly demonstrated that stressed animals more readily self-administer alcohol or other drugs. Similarly, human patients consistently report in clinical interviews that stress is one reason for taking drugs. There are also studies that document neurophysiological, neuroanatomical, neurochemical, and physiological changes to animals and humans who are stressed. Many of these changes occur within biological systems that are also affected by psychoactive drugs. Early response to stress also modifies neurodevelopment in permanent ways, and these neuroadaptations occur within the same neuronal systems which comprise the drug-reward circuit. But absent are studies in humans that link early stress and modifications of neurodevelopment with increased vulnerability to drug abuse. This article provides a glimpse of research relating stress to alteration of brain functions and to drug abuse, and points to the work of others in this volume for more details. We hope this attempt to understand how early stress affects the developing brain and increases vulnerability to drug abuse will lead to a new program of research in this emerging area.

Animals↗

PubMed2002

Maternal dietary docosahexanoic acid content affects the rat pup auditory system.

Previous studies of the effects of dietary docosahexanoic acid (DHA), 22:6n3, on neurodevelopment have focused mainly on visual-evoked potentials and indices of visual activity, measures that may be confounded by effects on the retina rather than on neural pathways. We investigated the effect of pre- and postnatal maternal dietary DHA content on auditory brainstem conduction times (ABCTs), the appearance of the auditory startle reflex (ASR), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) activity in brainstem homogenates. Timed pregnant dams were fed, beginning on day 2 of gestation and throughout lactation, a purified diet containing one of three levels of DHA (0, 1, or 3% of total fatty acids, or 0, 0.4 or 1.2% of total energy). On postnatal day (PND) 3, pups were randomly crossfostered within diet groups to minimize litter effects and culled to 10 per litter. Cerebrums and milk from culled pups stomachs were collected for lipid analysis. The timing of appearance of the ASR was determined between PND 10 through 14 and ABCTs were measured in pups on PND 24 and 31. Pups were sacrificed on PND 31 and cerebrums were removed. In each of two replicated studies, pups in the 1% DHA group weighed significantly less on PND 3 and they gained significantly less weight from PND 3 to 31 compared with pups in the 0 or 3% groups (p<0.01). The auditory studies were not conducted on the 1% DHA group since measures of auditory function are in part a function of somatic growth. The tissue fatty acid data for the 1% DHA group did not show unexpected findings. Higher dietary DHA was reflected in milk and pup cerebrums, and levels of arachidonic acid were inversely related to levels of DHA. In the pups of dams fed diets containing 3% versus 0% DHA, the ASR appeared significantly later (p<0.001) and the ABCTs were longer (p<0.05) on PND 31. CNPase activity levels were not different between the 0 and 3% DHA groups. This study demonstrated that the auditory brainstem response is sensitive for identifying effects of diet on neurodevelopment, and that diets supplemented with high levels of DHA may exert a negative influence on central nervous system development, potentially through effects on myelin. This study suggests the need for further studies of pre- and postnatal long chain polyunsaturated fatty acid dietary supplementation.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed1998

Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity.

Neuropilins bind secreted members of the semaphorin family of proteins. Neuropilin-1 is a receptor for Sema III. Here, we show that neuropilin-2 is a receptor for the secreted semaphorin Sema IV and acts selectively to mediate repulsive guidance events in discrete populations of neurons. neuropilin-2 and semaIV are expressed in strikingly complementary patterns during neurodevelopment. The extracellular complement-binding (CUB) and coagulation factor domains of neuropilin-2 confer specificity to the Sema IV repulsive response, and these domains of neuropilin-1 are necessary and sufficient for binding of the Sema III semaphorin (sema) domain. The coagulation factor domains alone are necessary and sufficient for binding of the Sema III immunoglobulin- (Ig-) basic domain and the unrelated ligand, vascular endothelial growth factor (VEGF). Lastly, neuropilin-1 can homomultimerize and form heteromultimers with neuropilin-2. These results provide insight into how interactions between neuropilins and secreted semaphorins function to coordinate repulsive axon guidance during neurodevelopment.

Animals↗

PubMed2003

Predictive value of EEG in neonates with periventricular leukomalacia.

The aim of this study was to evaluate whether EEG (i.e. positive Rolandic sharp waves) can be used to predict neurodevelopment in newborn infants with periventricular leukomalacia and compare the predictive value with that of MRI. A sequential cohort of neonates (n=45; 33 males, 12 females; mean gestational age 31.2 weeks, SD 2.7, range 27 to 37.8 weeks; mean birthweight 1592 g, SD 601 g) with periventricular hyperechogenicities on cranial ultrasound was recruited for this study. EEGs were analyzed for positive Rolandic sharp waves. Neurodevelopment was evaluated at the ages of 12 and 18 months. In the whole group the probability of a poor outcome was 24% and the probability of any impairment was 33%. If the number of positive Rolandic sharp waves was no more than 0.1 per minute, the probability of a poor outcome was reduced to 9% (95% confidence interval [95%CI] 2 to 27%) and the probability of any impairment was reduced to 13% (95%CI 4 to 32%). In all infants with more than 0.1 positive Rolandic sharp waves per minute the probability of a poor outcome was 41% (95%CI 23 to 61%) and of any impairment was 55% (95%CI 34 to 73%). In these infants MRI identified infants with a poor outcome with a sensitivity of 1.00 (95%CI 0.70 to 1.00) and a specificity of 0.92 (95%CI 0.67 to 0.99), and infants with any impairment with a sensitivity of 0.83 (95%CI 0.55 to 0.95) and a specificity of 1.00 (95%CI 0.72 to 1.00). Results suggest that if an EEG of an infant with periventricular leukomalacia contains no more than 0.1 positive Rolandic sharp waves per minute the probability of a normal or mildly delayed development is high (0.91, 95%CI 0.73 to 0.98). MRI enhances the accuracy of the outcome prediction slightly; however, owing to a wide confidence interval, this advantage is negligible. However, if the frequency of the positive Rolandic sharp waves exceeds 0.1per minute, MRI can significantly enhance the precision of the prediction of outcome.

Cohort Studies↗

PubMed2000

Role of maternal biochemistry in fetal brain development: effect of maternal thyroidectomy on behaviour and biogenic amine metabolism in rat progeny.

Few studies have addressed the role of biochemicals of maternal origin on fetal neurodevelopment and behavioural outcome. Thyroid deficiency in the thyroidectomized pregnant rat provides an excellent model to study fetal effects of maternal chemistry, as this condition is known to be associated with deficits in motor and cognitive behaviour in human offspring. Based on evidence that thyroid hormone of maternal origin may be an important determinant in regulating these behaviours, we assessed neurobehaviours and regional brain biogenic amine levels in offspring of rats thyroidectomized (Tx) prior to conception. Cross-fostering techniques were used to isolate fetal effects of maternal thyroid deficiency from possible neonatal effects during nursing by thyroid-deficient dams. The progeny of Tx dams showed significant deficits in maze learning, were less cautious in emotionality testing, and were more active in open-field exploration. Tx females appeared to be more vulnerable to the effects on learning. Learning in Tx males was only slightly impaired. Serotonin and dopamine metabolism was also affected in a brain region-specific manner in Tx progeny. Levels of 5-HIAA were reduced in the olfactory tubercle and cortex. HVA levels were lower in olfactory tubercle, but were elevated in the hippocampus. As these neurotransmitters play a functional role in activity, mood and learning, the findings may be pertinent to the observed behavioural impairments. The results are consistent with the hypothesis that an adequate in utero thyroid hormone environment may be essential for early fetal neurodevelopment even if the fetus is euthyroid.

Journal Article↗

PubMed2026

De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.

Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in gene regulation in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 16 de novo pathogenic variants in PCBP1 across 17 subjects from 16 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum disorder (ASD) as a prominent feature. Functional analysis in primary hippocampal mouse neuron cultures indicated that PCBP1 variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subject-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the contribution of PCBP1 in neurogenesis and neuritogenesis, which is impacted by loss-of-function variants expressed in neuronal cells, thereby supporting the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the prominent role of PCBP1 in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.

Journal Article↗

PubMed2026

Impact of NRSN2 deficiency on memory: Altered excitatory synaptic plasticity associated with reduced expression of NMDA receptor subunits and impaired LTP in the hippocampus.

Our earlier human studies identified NRSN2 (Neurensin-2), a neuronal-specific vesicular protein, as a candidate gene contributing to 20p13 microdeletion syndrome, yet the functional consequences of NRSN2 deficiency in the nervous system remain poorly understood. To explore the role of Nrsn2 in neurodevelopment and cognitive function, we utilized previously generated homozygous Nrsn2 knockout mice (Nrsn2-/-) and performed a series of behavioral, morphological, and electrophysiological analyses. Behaviorally, Nrsn2-/- mice exhibited mild locomotor impairment, as assessed by gait analysis at 4 and 8 weeks of age, as well as significant deficits in spatial learning and memory (Morris water maze) and fear memory (passive avoidance test) at 8 weeks. Morphometric analysis suggested no overt alterations in dendritic complexity or spine density in hippocampal CA1 pyramidal neurons or cerebellar Purkinje cells without developmental malformation. Electrophysiological recordings and immunoblotting analyses may reflect region-specific synaptic alterations. In the hippocampus, expression levels of the NMDA receptor subunits GluN1 and GluN2A were reduced at 4 weeks of age. Consistently, CA1 pyramidal neurons displayed decreased sEPSC frequency with unchanged amplitude under the conditions examined. In addition, an imbalance in hippocampal excitatory/inhibitory transmission was observed, as reflected by altered sEPSC frequency in the absence of changes in sIPSC frequency. In cerebellar Purkinje cells, GluA1-containing AMPA receptors were selectively downregulated, accompanied by reduced frequency and amplitude of sEPSCs and a selective decrease in sIPSC frequency, indicating both excitatory and inhibitory synaptic dysfunction in this region. Collectively, these findings indicate that Nrsn2 deficiency is accompanied by altered excitatory synaptic transmission and reduced long-term potentiation (LTP) at 8 weeks of age, despite preserved dendritic architecture as assessed by Golgi staining. These synaptic and plasticity deficits occur alongside the observed cognitive and motor impairments in Nrsn2⁻/⁻ mice. This study provides a descriptive phenotypic characterization of Nrsn2 deficiency and offers initial insights into the neurobiological role of NRSN2 and its contribution to neurodevelopment, learning, and memory.

Animals↗

PubMed1999

Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy.

BACKGROUND: Maternal thyroid function during early pregnancy is an important determinant of early fetal brain development because the fetal thyroid is unable to produce any T4 before 12-14 weeks' gestation. Overt maternal hypothyroidism as seen in severe iodine-deficient areas is associated with severely impaired neurological development of the offspring. At present, it is not known whether low free T4 (fT4) levels during pregnancy in healthy women from iodine sufficient areas may affect fetal neurodevelopment. METHODS: Neurodevelopment was assessed at 10 months of age in a cohort of 220 healthy children, born after uncomplicated pregnancies and deliveries, using the Bayley Scales of Infant Development. Maternal TSH, fT4 and TPO antibody status were assessed at 12 and 32 weeks' gestation. Maternal gestational fT4 concentration was defined as an independent parameter for child development. RESULTS: Children of women with fT4 levels below the 5th (< 9.8 pmol/l, n = 11) and 10th (< 10.4 pmol/l, n = 22) percentiles at 12 weeks' gestation had significantly lower scores on the Bayley Psychomotor Developmental Index (PDI) scale at 10 months of age, compared to children of mothers with higher fT4 values (t test, mean difference: 14.1, 95% confidence interval (CI): 5.9-22 and 7.4, 95% CI: 1.1-13.9, respectively). At 32 weeks' gestation, no significant differences were found. In the group of women with the lowest 10th percentile fT4 concentrations at 12 weeks' gestation, a positive correlation was found between the mothers' fT4 concentration and children's PDI scores (linear regression, R: 0.46, P = 0.03). After correction for confounding variables, a fT4 concentration below the 10th percentile at 12 weeks' gestation was a significant risk factor for impaired psychomotor development (RR): 5.8, 95% CI: 1.3-12.6). CONCLUSIONS: Low maternal plasma fT4 concentrations during early pregnancy may be an important risk factor for impaired infant development.

Antibodies↗