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PubMed2001

Variation of serotonergic gene expression: neurodevelopment and the complexity of response to psychopharmacologic drugs.

Individual differences in drug effects and treatment response are relatively enduring, continuously distributed, as well as substantially heritable, and are therefore likely to result from an interplay of multiple genomic variations with environmental influences. As the etiology and pathogenesis of behavioral and psychiatric disorders is genetically complex, so is the response to drug treatment. Psychopharmacologic drug response depends on the structure and functional expression of gene products, which may be direct drug targets or may indirectly modify the development and synaptic plasticity of neural networks critically involved in drug response. While formation and integration of these neural networks is dependent on the action of manifold proteins, converging lines of evidence indicate that genetically controlled variability in the expression of genes critical to the development and plasticity of distinct neurocircuits influences a wide spectrum of quantitative traits including treatment response. During brain development, neurotransmitter systems (e.g. serotonergic system), which are frequently targeted by psychotropic drugs, control neuronal specification, differentiation, and phenotype maintenance. The formation and maturation of these neurotransmitter systems, in turn, is directed by an intrinsic genetic program. Based on the notion that complex gene-gene and gene environment interactions in the regulation of brain plasticity are presumed to contribute to interindividual differences in drug response, the concept of developmental psychopharmacogenetics is emerging. This review appraises prototypical genomic variation with impact on gene expression and complementary studies of genetic and environmental effects on brain development and synaptic plasticity in the mouse model. Although special emphasis is given to molecular mechanisms of neurodevelopmental genetics, relevant conceptual and methodological issues pertinent to the dissection of the psychopharmacogenetic-neurodevelopmental interface are also considered.

Animals↗
PubMed1997

Schizophrenia: a disorder of neurodevelopment?

For the first time, there is a pathogenic hypothesis of schizophrenia based upon reasonable empirical data. The hypothesis is that schizophrenia is a disorder arising from aberrant brain development. The neurodevelopmental view of schizophrenia is supported by neuropathological, epidemiological and clinical findings. Here, the evidence in favour of the model is summarized, together with a consideration of its weaknesses.

Brain↗
PubMed1999

Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age.

The aim of the study was to test the hypotheses that elevated cerebral lactate, detected by proton spectroscopy performed within 18 hours of suspected birth asphyxia, is associated with adverse outcome, and that increased lactate can be used to predict adverse outcome. Thirty-one term infants suspected of having had birth asphyxia and seven control infants underwent proton magnetic resonance spectroscopy, using three-dimensional chemical shift imaging, within 18 hours of birth. Adverse outcome was defined as death or neurodevelopmental impairment at 1 year of age or more. Nine infants had an adverse outcome. The other 22 and all of the control infants remained normal. Median (range) lactate/creatine plus phosphocreatine (lactate/creatine) ratios in the abnormal, the normal, and the control group were 1.14 (0.17 to 3.81), 0.33 (0 to 1.51), and 0.05 (0 to 0.6) respectively (P=0.003). Lactate/creatine >1.0 predicted neurodevelopmental impairment at 1 year of age with sensitivity of 66% and specificity of 95%, positive and negative predictive values of 86% and 88%, and a likelihood ratio of 13.2. Elevated cerebral lactate/creatine within 18 hours of birth asphyxia predicts adverse outcome.

Asphyxia Neonatorum↗
PubMed2002

Cycling at the interface between neurodevelopment and neurodegeneration.

The discovery of cell cycle regulators has directed cell research into uncharted territory. In dividing cells, cell cycle-associated protein kinases, which are referred to as cyclin-dependent-kinases (Cdks), regulate proliferation, differentiation, senescence and apoptosis. In contrast, all Cdks in post-mitotic neurons, with the notable exception of Cdk5, are silenced. Surprisingly, misregulation of Cdks occurs in neurons in a wide diversity of neurological disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Ectopic expression of these proteins in neurons potently induces cell death with hallmarks of apoptosis. Deregulation of the unique, cell cycle-unrelated Cdk5 by its truncated co-activator, p25 and p29, contributes to neurodegeneration by altering the phosphorylation state of non-membrane-associated proteins and possibly through the induction of cell cycle proteins. On the other hand, cycling Cdks such as Cdk2, Cdk4 and Cdk6, initiate death pathways by derepressing E2F-1/Rb-dependent transcription at the neuronal G1/S checkpoint. Thus, Cdk5 and cycling Cdks may have little in common in the healthy CNS, but they likely conspire in leading neurons to their demise.

Animals↗
PubMed2005

Risk factors for adverse neurodevelopment in extremely low birth weight infants with normal neonatal cranial ultrasound.

OBJECTIVES: To determine risk factors associated with adverse developmental outcome at 5 years in extremely low birth weight infants or extremely premature infants (<28 weeks) with normal neonatal cranial ultrasounds. DESIGN/METHODS: Data were collected prospectively on 152 infants with gestation <28 weeks or birth-weight <1000 g. Infants were grouped into those with normal development, mild-to-moderate impairment (IQ 70 to 84, or hearing loss 30 to 89 dB, visual acuity 6/18 to 6/60, or mild/moderate cerebral palsy (CP)) and severe impairment (IQ <70, hearing loss > or =90 dB, visual acuity <6/60, or severe CP). RESULTS: Five-year outcomes were available for 144/152 children (95%). In all, 89 (62%) infants had normal development, 39 (27%) had mild-moderate impairment and 16 (11%) had severe impairment. On multivariate logistic regression analysis, factors associated with developmental impairment were serum bilirubin > or =200 micromol/l (odds ratio (OR) - 4.06, p=0.003) and retinopathy of prematurity (ROP) (OR - 1.6, p=0.03). CONCLUSIONS: A serum bilirubin > or =200 micromol/l and presence of ROP are postnatal risk factors associated with an adverse developmental outcome in infants with normal cranial ultrasounds.

Bilirubin↗
PubMed2001

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms.

The task of defining schizophrenia pathogenesis has fascinated and frustrated researchers for nearly a century. In recent years, unprecedented advances from diverse fields of study have given credence to both viral and developmental theories. This review considers possible mechanisms by which viral and developmental processes may interact to engender schizophrenia. Many of the current controversies in schizophrenia pathogenesis are reviewed in light of the viral hypothesis, including: epidemiological findings and the role of a genetic diathesis, phenotype heterogeneity, abnormalities in excitatory and inhibitory neurotransmitter systems, anomalous cerebral latereralization, and static vs progressive disease. The importance of animal models in elucidating the impact of viral infections on developing neurons is illustrated by recent studies in which neonatal rats are infected with lymphocytic choriomeningitis virus in order to examine alterations in hippocampal circuitry. Finally, consideration is given to a new hypothesis that some cases of schizophrenia could be instigated by a viral infection that disrupts developing inhibitory circuits, consequently unleashing glutamatergic neurotransmission leading to selective excitotoxicity, and a degenerative disease course.

Animals↗
PubMed2003

Schizophrenia, neurodevelopment and corpus callosum.

The Zeitgeist favors an interpretation of schizophrenia as a condition of abnormal connectivity of cortical neurons, particularly in the prefrontal and temporal cortex. The available evidence points to reduced connectivity, a possible consequence of excessive synaptic pruning in development. A decreased thalamic input to the cerebral cortex appears likely, and developmental studies predict that this decrease should entail a secondary loss of both long- and short-range cortico-cortical connections, including connections between the hemispheres. Indeed, morphological, electrophysiological and neuropsychological studies over the last two decades suggest that the callosal connections are altered in schizophrenics. However, the alterations are subtle and sometimes inconsistent across studies, and need to be investigated further with new methodologies.

Agenesis of Corpus Callosum↗
PubMed2004

Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment.

Disrupted in Schizophrenia 1 (DISC1) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have recently presented evidence that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel. In this study, we report the protein expression profile of DISC1 in the adult and developing mouse brain utilizing immunohistochemistry and quantitative Western blot. In the adult mouse brain, DISC1 is expressed in neurons within various brain areas including the olfactory bulb, cortex, hippocampus, hypothalamus, cerebellum and brain stem. During development, DISC1 protein is detected at all stages, from E10 to 6 months old, with two significant peaks of protein expression of a DISC1 isoform at E13.5 and P35. Interestingly, these time points correspond to critical stages during mouse development, the active neurogenesis period in the developing brain and the period of puberty. Together, these results suggest that DISC1 may play a critical role in brain development, consistent with the neurodevelopmental hypothesis of the etiology of schizophrenia.

Animals↗
PubMed2002

Erythropoietin and the brain: from neurodevelopment to neuroprotection.

It is now widely known that erythropoietin (Epo) does not only affect the haematopoietic system, but it can be considered a multifunctional trophic factor with an effect on the general homoeostasis of the entire organism. The recent discovery of a specific Epo/Epo-receptor system in the central nervous system (CNS) and cerebrospinal fluid, independently of the haematopoietic system, has further paved the way for new studies aimed at investigating the different sites of cerebral expression of Epo and its receptor, the regulation of their expression and, finally, the effects that this hormone has on the development and maturation of the brain. A further aim has been to investigate how it influences CNS homoeostasis and neurotransmission in adult brain. Attention has also been focused on the neurotrophic and neuroprotective function of Epo in different conditions of neuronal damage, such as hypoxia, cerebral ischaemia and subarachnoid haemorrhage, and therefore on the possibility that human recombinant Epo therapy could soon be used in clinical practice, also to limit neuronal damage induced by these diseases.

Animals↗
PubMed1998

Congenital hypothyroidism in Wales (1982-1993): demographic features, clinical presentation and effects on early neurodevelopment.

OBJECTIVE: Neonatal screening for congenital hypothyroidism (CH) was introduced in Wales in 1982. The aim of the study was to evaluate the demographic features and characteristics of infants identified during the first 12 years of screening and their neurodevelopmental progress in the first 2 years of life. DESIGN: Prospective collection of biochemical and clinical data (including results of Griffiths Mental Development Scales) obtained from questionnaires sent to paediatricians responsible for the ongoing clinical care of children with CH. PATIENTS: In Wales, between 1982 and 1993, 136 infants with primary congenital hypothyroidism (CH) were identified by the neonatal screening programme. RESULTS: Of all new-borns, 99.8% were screened and the prevalence of CH was 1 in 3279 (1 in 2473 girls and 1 in 4770 boys). The prevalence of CH was increased in North Wales. CH was associated with increased birth weight (48.5% of infants weighed greater than 3.5 kg) and an increased prevalence of non-thyroidal congenital abnormalities (8%) and congenital heart disease (3%). Isotope scanning demonstrated an increased prevalence of normal or enlarged thyroid glands and fewer ectopic glands compared to those reported in other studies. The mean developmental quotients (DQs) for individual subsets of intellectual and behavioural functioning in children with CH aged 1 and 2 years were all above 100 (range: 103.5-111.9). In subjects with absent thyroids, these DQs were correlated with the serum concentrations of free thyroxine before treatment. CONCLUSIONS: The demographic features of infants with congenital hypothyroidism born in Wales are similar to those reported from other European studies although there are marked regional variations in prevalence within Wales for which there is no apparent explanation. The median age of starting therapy was 17 days and compares favourably with other screening programmes. The overall mental development of Welsh children aged 1 and 2 years with congenital hypothyroidism identified by neonatal screening is satisfactory.

Congenital Abnormalities↗
PubMed2003

Term infant studies of DHA and ARA supplementation on neurodevelopment: results of randomized controlled trials.

Healthy term infants who are not breast-fed may need long-chain polyunsaturated fatty acids (LCPUFA) in their feeding, based on the changes in plasma and tissue fatty composition. However, consistent functional effects across different studies conducted over the past two decades has been more difficult to document. The interpretation of these data has scientific and public interest with the introduction of LCPUFA supplemented formula. There are 14 controlled trials in term infants that have included formula feeding with or without LCPUFA and functional assessment of visual and other measures of neural development; in addition, 7 have evaluated specific measures related to cognitive development. We chose to examine the effect of DHA dose provided daily on the development of visual acuity to explain the differences in visual acuity responses across randomized studies. A "meta-regression" was performed with the use of a DHA effective dose as the independent variable and visual acuity at 4 months as the dependent variable. Since the two main dietary determinants of DHA status are the LNA provided and the preformed DHA consumed, we defined DHA equivalent dose across studies by assuming a 1%, 5%, and 10% conversion of LNA to DHA. Results indicate a strong and significant effect of DHA equivalent dose on magnitude of the visual acuity response at all conversions tested; greatest significance was found when using a 10% bioequivalency (r(2)=0.68, and P=.001). We conclude that there is a significant relation between the total DHA equivalents provided and effectiveness as defined by visual acuity measurements at 4 months of age.

Age Factors↗
PubMed2001

Pregnancy in adolescent rats, growth and neurodevelopment in their offspring.

Pregnancy, lactation and the relationship between mother and their offspring in adolescence was studied in terms of pups neurosomatic development. The frequency of conception and birth rate were reduced in adolescent dams. Their body weight gain was accelerated during the first two weeks of pregnancy, while a significant delay occurred in the third week. At birth, plasma corticosterone level in the neonates was increased. Adolescent dams ingested less food during the first week of gestation. Following that, till the second week of lactation, the food consumption was equal to that of control group. Although adolescent pups were heavier at birth, the reduction of their number and of their body weight occurred during lactation. Judging by appearance of grasping, righting, placing and of negative geotaxis reflexes, the delay in their neurological maturation was also present. The reason for the growth and neurodevelopmental delay during lactation is probably the result of malnutrition and stress of disturbed mother - infant relationship in adolescent litters, which lasted at least during the two postnatal weeks. It was indicated by the resting plasma corticosterone levels during the first two postnatal weeks. This finding suggests that the pregnancy in adolescent rats induces delay in physical and neurological development, as well as in the increased rate of postnatal mortality of their offspring.

Animals↗
PubMed2005

Early maternal deprivation retards neurodevelopment in Wistar rats.

A single 24 h period of maternal deprivation (MD) in rats has been shown to induce, in adulthood, a number of abnormalities in brain and behaviour that also occur in patients with schizophrenia. However, the short-term behavioural effects of MD have not been studied in detail. Since patients with schizophrenia are characterized by a retardation of normal development, we aimed in the present study to investigate the development of control rats and rats that were exposed to MD on postnatal day 9. Compared to control animals, MD rats showed (1) a reduction in body weight, (2) an increased in reversal latency in negative geotaxis, (3) a delayed eye opening, (4) a delayed emergence of walking and rearing; and (5) a delayed emergence of the behavioural response to amphetamine (amph). On the other hand, MD and control rats responded similarly to the non-competitive NMDA antagonist MK801. These data clearly show that early MD delays development, especially of the dopaminergic system and confirm our hypothesis that MD may represent an interesting animal model for the neurodevelopmental hypothesis of schizophrenia.

Amphetamine↗
PubMedDate not supplied

Schizophrenia and bipolar disorder are distinguished mainly by differences in neurodevelopment.

This paper examines the commonalities and the differences between schizophrenia and bipolar disorder. Recent studies suggest a possible overlap in genetic susceptibility to the two conditions. However, while the influence of early environmental effects, particularly obstetric complications, has been established for schizophrenia, no such replicable association with bipolar disorder has been found. Structural abnormalities of the brain have been identified in both schizophrenia and bipolar disorder, but while the volume of the amygdala and hippocampus appears decreased in schizophrenia, this is not the case in bipolar disorder; indeed there are some suggestions of increased volume of the amygdala. Furthermore, schizophrenia is characterised by lower IQ, executive function and verbal memory, but there is little evidence of trait neuropsychological deficits in bipolar disorder. Similarly, premanic children do not show the cognitive and neuromotor impairments characteristic of those destined to develop schizophrenia. The most plausible explanation is that the two conditions share some genetic predisposition but differ in that schizophrenia but not bipolar disorder is subject to additional genes or early environmental hazards causing neurodevelopmental impairment.

Journal Article↗
PubMedDate not supplied

Multimodal neuroimaging studies and neurodevelopment and neurodegeneration hypotheses of schizophrenia.

The interpretation of the huge number of results in schizophrenia research using neuroimaging is uncertain. However, the simultaneous use of complimentary data obtained with these techniques may yield more relevant information in this regard. In this paper we present a series of studies performed by our group in two schizophrenic samples with the use of structural (magnetic resonance imaging, MRI), functional [glucose positron emission tomography (PET) and N-acetyl-aspartate (NAA) magnetic resonance spectrocopy] and neurophysiological techniques (the P300 event-related potential). Transversal and longitudinal measurements were performed.The integrated vision of the results so obtained allows us to propose the hypothesis of a neurodevelopmentally determined state of prefrontal disinihibition, in which the degree of atrophy would directly relate to the metabolic rate. This state would already be present in the first stages of illness and could have neurotoxic consequences in the long term. This would explain the findings of an association between sulcal cerebrospinal fluid (CSF) and illness duration and decreased NAA levels in chronic but not in recent-onset cases. The prefrotnal disinhibition would overstimulate the limbic system and the hippocampus would become overactivated, the metabolic rate at this level being inversely related to P300 amplitude. Clozapine showed a more selective and intense action on that hyperactive metabolic tone than haloperidol.

Journal Article↗