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Results for “Neurodevelopmental Disorders”

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PubMed2006

Central nervous changes in social dysfunction: autism, aggression, and psychopathy.

Neurodevelopmental disorders such as autism and schizophrenia involve social interaction problems and poor mentalizing abilities, associated with abnormal regional cerebral activity. Similar problems may be present in aggressive personality disorders and psychopathy. This paper reviews brain imaging data from research aiming at establishing possible central nervous correlates to aggression and psychopathy. Studies in this field are associated with a range of method problems. Differences between criminal offenders and controls may be confounded by a number of factors unrelated to personality traits or aggression per se. Phenotypical characterisation varies between studies as do the laboratory methods and their interpretation. In spite of these problems, there are some recurrent findings in the present literature. Hypoactivity or structural reduction of the prefrontal cortex is a consistent finding in violent offenders or subjects with antisocial personality disorder. When defined as a personality disorder of social interaction and empathy, psychopathy seems to be associated rather with central abnormalities in the limbic circuitry. Indications of an increased dopaminergic neurotransmission relative to the serotonergic have also been connected to such personality traits, especially to the AD/HD-related behavioural aspects. Further studies using strict phenotypical definitions or experimental models are clearly warranted to establish a pathophysiological background to destructive personality traits and the propensity to violent acting out.

Aggression↗

PubMed2007

Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.

The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of alpha-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders.

Amino Acid Sequence↗

PubMed2005

Visual magnocellular and structure from motion perceptual deficits in a neurodevelopmental model of dorsal stream function.

Williams syndrome (WS) is a neurodevelopmental disorder of genetic origin that has been used as a model to understand visual cognition. We have investigated early deficits in the afferent magnocellular pathway and their relation to abnormal visual dorsal processing in WS. A spatiotemporal contrast sensitivity task that is known to selectively activate that pathway was used in six WS subjects. Additionally, we have compared visual performance in 2D and 3D motion integration tasks. A novel 3D motion coherence task (using spheres with unpredictable axis of rotation) was used in order to investigate possible impairment of occipitoparietal areas that are known to be involved in 3D structure from motion (SFM) perception. We have found a significant involvement of low-level magnocellular maps in WS as assessed by the contrast sensitivity task. On the contrary, no significant differences were observed between WS and the control groups in the 2D motion integration tasks. However, all WS subjects were significantly impaired in the 3D SFM task. Our findings suggest that magnocellular damage may occur in addition to dorsal stream deficits in these patients. They are also consistent with recently described genetic and neuroanatomic abnormalities in retinotopic visual areas. Finally, selective SFM coherence deficits support the proposal that there is a specific pathway in the dorsal stream that is involved in motion processing of 3D surfaces, which seems to be impaired in this disorder.

Adolescent↗

PubMed2005

Transcriptional control of cognitive development.

Cognitive development is determined by both genetics and environment. One point of convergence of these two influences is the neural activity-dependent regulation of programs of gene expression that specify neuronal fate and function. Human genetic studies have linked several transcriptional regulators to neurodevelopmental disorders including mental retardation and autism spectrum disorders. Recent reports on two such factors, CREB-binding protein and methyl-CpG-binding protein 2, have begun to reveal how epigenetics and neuronal activity act to modulate the program of gene expression required for synaptic development and function.

Animals↗

PubMed2006

Enhanced cognitive control in young people with Tourette's syndrome.

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by the presence of chronic vocal and motor tics. Tics are sudden, highly stereotyped, movements that can be simple or complex in appearance. Since patients with TS have difficulties preventing unwanted movements, one might expect that their ability to voluntarily control goal-directed movements would be similarly poor. Indeed, it has been suggested that TS sufferers are impaired at inhibiting reflexively triggered movements and in rapidly selecting or switching between different motor sets. This idea is consistent with current views on the neurological basis of TS that posit a dysfunction of the neural circuits linking the frontal lobes and the striatum. These circuits are known to be involved in the voluntary control of action. By using an oculomotor switching task, we show for the first time that young people with TS exhibit paradoxically greater levels of cognitive control over their movements than their age-matched controls. This finding is consistent with an increased need to monitor and control movements and may indicate a subcortical locus for the triggering of tics. It also suggests that the constant need to suppress tics could have resulted in an enhancement of the executive processes involved in inhibitory control.

Adolescent↗

PubMed2006

MeCP2-dependent transcriptional repression regulates excitatory neurotransmission.

Mutations in the transcriptional repressor, methyl-CpG binding protein 2 (MeCP2), result in a neurodevelopmental disorder called Rett Syndrome (RTT) . Based on the neurological phenotypes observed in Rett patients, we examined the potential role of MeCP2 in synaptic function. We compared elementary properties of synaptic transmission between cultured hippocampal neurons from MeCP2 knockout and wild-type littermate control mice and found a decrease in the frequency of spontaneous excitatory synaptic transmission (mEPSCs) in neurons lacking MeCP2. We also detected a significant increase in the rate of short-term synaptic depression. To explore whether these functional effects can be attributed to MeCP2's role as a transcriptional silencer, we treated cultures with a drug that impairs histone deacetylation and examined spontaneous synaptic transmission. Treatment with this compound induced a similar decrease in mEPSC frequency in wild-type control cultures, but this decrease was occluded in MeCP2-deficient neurons. Interestingly, neither the loss of MeCP2 nor the drug treatment resulted in changes in mIPSC properties. Finally, by means of a lentivirus expressing Cre recombinase, we show that loss of MeCP2 function after neurodevelopment and synaptogenesis was sufficient to mimic the decrease in mEPSC frequency seen in constitutive MeCP2 KO neurons. Taken together, these results suggest a role for MeCP2 in control of excitatory presynaptic function through regulation of gene expression.

Animals↗

PubMed2026

Carotid body dysfunction contributes to respiratory instability in Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2. Disordered breathing is a hallmark feature of RTT that negatively impacts quality of life and can be life-threatening. Despite this, the mechanisms underlying disordered breathing in RTT are poorly understood. Although RTT is primarily considered a central nervous system disorder, we found that increased drive from peripheral respiratory chemoreceptors may contribute to unstable breathing in MeCP2-deficient mice. Consistent with this, breathing pure oxygen to limit the output of peripheral chemoreceptors stabilized breathing in MeCP2-deficient mice. Also, knockdown of MeCP2 within the carotid body recapitulates RTT-like unstable breathing. We also found that MeCP2 deficiency alters the carotid body transcriptome, including the disruption of genes involved in dopaminergic signaling, and treatment with a dopamine receptor agonist stabilized breathing in MeCP2-deficient mice. These results identify the peripheral chemoreceptors as high-priority therapeutic targets for disordered breathing in RTT.

carotid body↗

PubMed2005

GABAA receptor beta3 subunit gene-deficient heterozygous mice show parent-of-origin and gender-related differences in beta3 subunit levels, EEG, and behavior.

The homozygous knockout mouse for the beta3 subunit of the GABAA receptor has been proposed as a model for the neurodevelopmental disorder, Angelman syndrome, based on phenotypic similarities of craniofacial abnormalities, cognitive defects, hyperactivity, motor incoordination, disturbed rest-activity cycles, and epilepsy. Since most children with Angelman syndrome are autosomal heterozygotes of maternal origin, apparently through genomic imprinting, we used gabrb3-deficient heterozygote mice of defined parental origin to investigate whether this phenotype is also maternally imprinted in mouse. Whole brain extracts showed greatly reduced beta3 subunit levels in male mice of maternal origin but not in male mice of paternal origin. Females of both parental origin showed greatly reduced beta3 subunit levels. Heterozygotes did not exhibit hyperactive circling behavior, convulsions, or electrographically recorded seizures. EEGs showed qualitative differences among heterozygotes, with male mice of maternal origin demonstrating more abnormalities including increased theta activity. Ethosuximide inhibited theta bursts, suggesting an alteration in the thalamocortical relay. Carbamazepine induced EEG slowing in males and EEG acceleration in females, with a larger effect in paternal-origin heterozygotes. Evidence thus suggests both parent-of-origin and gender-related components in developmental regulation of beta3 expression, in particular, that the maternally-derived male heterozygote may carry a developmental modification resulting in less beta3 protein, which may reflect partial genomic imprinting of the gabrb3 gene in mice.

Angelman Syndrome↗

PubMed2005

Embryonic cerebellar granule cells are resistant to necrosis induced by homocysteine.

Hyperhomocysteinemia is a risk factor for a range of neurodegenerative conditions, yet its effects in the developing nervous system have been poorly elucidated. We studied the in vitro response of cerebellar granule neurons (CGCs) to homocysteine. We have shown that embryonic CGCs are resistant to homocysteine-induced neurotoxicity, whilst postnatal CGCs are not. This is the first demonstration of a neuronal population undergoing a developmental switch in their response to homocysteine. Greater understanding of this change may have important implications for both neurodegenerative conditions and neurodevelopmental disorders.

Aging↗

PubMed2024

Mast cells proliferate in the peri-hippocampal space during early development and modulate local and peripheral immune cells.

Brain development is a non-linear process of regionally specific epochs occurring during windows of sensitivity to endogenous and exogenous stimuli. We have identified an epoch in the neonatal rat brain defined by a transient population of peri-hippocampal mast cells (phMCs) that are abundant from birth through 2-weeks post-natal but absent thereafter. The phMCs are maintained by proliferation and harbor a unique transcriptome compared with mast cells residing in the skin, bone marrow, or other brain regions. Pharmacological activation of this population broadly increases blood-brain barrier permeability, recruits peripheral immune cells, and stunts local microglia proliferation. Examination of the post-mortem human brain demonstrated mast cells in the peri-hippocampal region of a newborn, but not an older infant, suggesting a similar developmental period exists in humans. Mast cells specifically, and early-life inflammation generally, have been linked to heightened risk for neurodevelopmental disorders, and these results demonstrate a plausible source of that risk.

Mast Cells↗

PubMed2026

The role of CHAMP1 in chromatin-mediated DNA damage repair.

Defects in the replication stress response are major drivers of cancer development and present key targetable vulnerabilities that can be exploited for anti-cancer therapy. Recent studies have identified CHAMP1 as a novel DNA damage repair factor with roles in double-strand break repair and the replication stress response. Mutations in CHAMP1 are associated with the neurodevelopmental disorder CHAMP1 Syndrome. More recently, children with CHAMP1 Syndrome have developed leukemia, suggesting that CHAMP1 mutations are a potential cancer risk factor. CHAMP1 is part of two DNA damage repair complexes: CHAMP1-POGZ-REV7 (Complex I) and CHAMP1-POGZ-HP1α (Complex II). Complex I promotes homologous recombination by removing the Shieldin complex from the ends of double strand breaks and allowing DSB end resection to occur. Complex II enriches heterochromatin content through the recruitment of the methyltransferase SETDB1 to DNA damage sites. Increased heterochromatin at stalled forks is associated with proper fork stability and restart, demonstrating the importance of CHAMP1 in maintaining genomic integrity. Loss of CHAMP1 leads to increased sensitivity to DNA damaging agents and increased dependence on other DNA damage repair pathways, such as the DNA damage checkpoint and the Fanconi Anemia pathway. CHAMP1 is overexpressed in breast and ovarian cancer cells with high levels of replication stress, providing a molecular mechanism for the tolerance of replication stress. These new findings on the relationship of CHAMP1 with well-established DNA damage repair pathways, suggest that targeting CHAMP1 could present a new synthetic lethality opportunity for cancer cells with high levels of replication stress.

CHAMP1↗

PubMed2006

Detection of a deletion of exons 8-16 of the UBE3A gene in familial Angelman syndrome using a semi-quantitative dosage PCR based assay.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by failure of expression of the maternal copy of the imprinted UBE3A gene through a variety of mechanisms detected by methylation studies, mutation analysis of UBE3A and FISH. In 10-15% of suspected cases of AS these investigations do not reveal a genetic abnormality. We report here the development of a semi-quantitative dosage PCR technique used to identify sub-microscopic deletions involving UBE3A. Using this method we analysed a panel of 26 patients from 24 families, all fulfilling the clinical criteria for AS. We identified a deletion of UBE3A exons 8-16 in a sibling pair. Analysis of parental samples revealed the same deletion in their phenotypically normal mother. This is an inexpensive and valuable method for detecting UBE3A deletions in a small but important proportion of AS cases of unidentifiable cause.

Adolescent↗

PubMed2005

Evolution of primary microcephaly genes and the enlargement of primate brains.

Brain size, in relation to body size, has varied markedly during the evolution of mammals. In particular, a large cerebral cortex is a feature that distinguishes humans from our fellow primates. Such anatomical changes must have a basis in genetic alterations, but the molecular processes involved have yet to be defined. However, recent advances from the cloning of two human disease genes promise to make inroads in this important area. Microcephalin (MCPH1) and Abnormal spindle-like microcephaly associated (ASPM) are genes mutated in primary microcephaly, a human neurodevelopmental disorder. In this 'atavistic' condition, brain size is reduced in volume to a size comparable with that of early hominids. Hence, it has been proposed that these genes evolved adaptively with increasing primate brain size. Subsequent studies have lent weight to this hypothesis by showing that both genes have undergone positive selection during great ape evolution. Further functional characterisation of their proteins will contribute to an understanding of the molecular and evolutionary processes that have determined human brain size.

Animals↗

PubMed2026

Transcriptomic landscape of microglia in mouse models of social dysfunction and oxytocin-mediated recovery.

Atypical sociability is a hallmark of neurodevelopmental disorders arising from genetic susceptibility and prenatal environmental perturbations that can affect diverse brain cell types. Using single-cell transcriptomics, we previously identified selective vulnerability of parvocellular oxytocin (OT) neurons in the paraventricular hypothalamus (PVH) following embryonic exposure to valproic acid (VPA), a teratogen that induces social deficits. Neonatal chemogenetic activation of OT neurons rescued these behavioral abnormalities and partially restored dysregulated gene expression. However, the effects of VPA exposure and OT neuron stimulation on non-neuronal PVH cells remained unclear. Here, we show that VPA induces transcriptional abnormalities in PVH microglia. Spatial transcriptomics revealed altered distributions of PVH microglial subtypes. Notably, neonatal OT neuron stimulation reversed a subset of VPA-induced microglial gene downregulation, while pharmacological manipulation of microglia normalized aberrant OT gene expression in putative parvocellular OT neurons. These findings support bidirectional OT neuron-microglia interactions that may underlie social dysfunction following embryonic VPA exposure.

autism spectrum disorder↗

PubMed2004

The transcriptional repressor Mecp2 regulates terminal neuronal differentiation.

Rett syndrome (RTT) is a severe neurodevelopmental disorder with features of autism that results from mutation of the gene encoding the transcriptional repressor methyl-CpG binding protein (MECP2). The consequences of loss of a transcription factor may be complex, affecting the expression of many proteins, thus limiting understanding of this class of diseases and impeding therapeutic strategies. This is true for RTT. Neither the cell biological mechanism(s) nor the developmental stage affected by MECP2 deficiency is known. In vivo analysis of the olfactory system demonstrates that Mecp2 deficiency leads to a transient delay in the terminal differentiation of olfactory neurons. This delay in maturation disrupts axonal targeting in the olfactory bulb, resulting in abnormal axonal projections, subglomerular disorganization, and a persistent reduction in glomerular size. These results indicate a critical cell biological function for Mecp2 in mediating the final stages of neuronal development.

Animals↗

PubMed2004

MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions.

Rett syndrome is a neurodevelopmental disorder and one of the causes of mental retardation and autistic behavior in girls, as well as in a small group of boys. It was recently discovered that mutation of the methyl-CpG-binding protein 2 (MECP2) gene encoding a transcriptional repressor on the X chromosome causes Rett syndrome. Although it is evident that phenotypes of MECP2 mutant mice that resemble those of Rett syndrome are attributable to lack of the MECP2 gene in the central nervous system (CNS), there is little understanding of the neuropathological abnormalities in the CNS of MECP2-null mice. Here, we investigated the developmental regulation and specific cellular expression of MECP2 during neural development both in vitro and in vivo. MECP2 is expressed in mature neurons, but not in astroglia or oligodendroglia, and is increasingly expressed during development of the mouse neocortex. In addition, in vitro culture studies suggest that MECP2 is expressed in more differentiated neurons rather than in less differentiated neuroblasts. Under in vitro conditions using neural precursor cultures, we find that MECP2 mutant neural precursors differentiate into morphologically mature neurons and glia, and no significant differences in differentiation are detected between cells from wild-type and MECP2 mutant mice, suggesting that MECP2 may play a different role in mice than it does in Xenopus embryos. In agreement with this hypothesis, neocortical projection layers in MECP2 -/y mice are thinner than those in wild-type mice, and pyramidal neurons in layer II/III in MECP2 -/y mice are smaller and less complex than those in wild-type mice. Taken together, our results indicate that MECP2 is involved in the maturation and maintenance of neurons, including dendritic arborization, rather than in cell fate decisions.

Animals↗

PubMed2005

Automatic segmentation of MR images of the developing newborn brain.

This paper describes an automatic tissue segmentation method for newborn brains from magnetic resonance images (MRI). The analysis and study of newborn brain MRI is of great interest due to its potential for studying early growth patterns and morphological changes in neurodevelopmental disorders. Automatic segmentation of newborn MRI is a challenging task mainly due to the low intensity contrast and the growth process of the white matter tissue. Newborn white matter tissue undergoes a rapid myelination process, where the nerves are covered in myelin sheathes. It is necessary to identify the white matter tissue as myelinated or non-myelinated regions. The degree of myelination is a fractional voxel property that represents regional changes of white matter as a function of age. Our method makes use of a registered probabilistic brain atlas. The method first uses robust graph clustering and parameter estimation to find the initial intensity distributions. The distribution estimates are then used together with the spatial priors to perform bias correction. Finally, the method refines the segmentation using training sample pruning and non-parametric kernel density estimation. Our results demonstrate that the method is able to segment the brain tissue and identify myelinated and non-myelinated white matter regions.

Aging↗

PubMed2004

Thimerosal and autism? A plausible hypothesis that should not be dismissed.

The autism-mercury hypothesis first described by Bernard et al. has generated much interest and controversy. The Institute of Medicine (IOM) reviewed the connection between mercury-containing vaccines and neurodevelopmental disorders, including autism. They concluded that the hypothesis was biologically plausible but that there was insufficient evidence to accept or reject a causal connection and recommended a comprehensive research program. Without citing new experimental evidence, a number of observers have offered opinions on the subject, some of which reject the IOM's conclusions. In a recent review, Nelson and Bauman argue that a link between the preservative thimerosal, the source of the mercury in childhood vaccines, is improbable. In their defense of thimerosal, these authors take a narrow view of the original hypothesis, provide no new evidence, and rely on selective citations and flawed reasoning. We provide evidence here to refute the Nelson and Bauman critique and to defend the autism-mercury hypothesis.

Autistic Disorder↗