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PubMed2026

A massively parallel CRISPR-based screening platform for modifiers of neuronal depolarization.

Understanding the complex interplay between gene expression and neuronal activity is crucial for unraveling the molecular mechanisms underlying cognitive function and neurological disorders. Here, we developed pooled screens using CRISPR interference (CRISPRi) and the fluorescent calcium integrator CaMPARI2 to evaluate genetic modifiers of neuronal depolarization. Using this screening method, we evaluated 1343 genes for their effect on depolarization in a human iPSC-derived neuron model, revealing potential links to neurodegenerative and neurodevelopmental disorders. These genes include known regulators of neuronal excitability, such as TARPs and ion channels, as well as genes associated with autism spectrum disorder and Alzheimer's disease not previously described to affect neuronal depolarization. This CRISPRi-based screening platform offers a versatile tool to uncover molecular mechanisms controlling neuronal function in health and disease.

Humans↗

PubMed1995

Reversal of asymmetry of the planum temporale in schizophrenia.

OBJECTIVE: The planum temporale is intimately involved in the generation and understanding of language and has been suggested to be a key area affected in schizophrenia. To explore temporal lobe abnormalities in schizophrenia, the authors measured the planum temporale, a normally asymmetric area lying on the superior part of the temporal lobe, in schizophrenic patients. METHOD: High-resolution magnetic resonance imaging (MRI) scans were obtained for 14 right-handed schizophrenic patients and 14 healthy comparison subjects individually matched for age, sex, handedness, race, and parental socioeconomic status. The surface area of the planum temporale was measured by using MRI reconstruction techniques. RESULTS: There was striking reversal of the normal asymmetry (left larger than right) in planum temporale surface area in 13 of the schizophrenic patients but in only two of the comparison subjects. However, Heschl's gyrus (primary sensory cortex), which served as an anatomically contiguous nonheteromodal cortical comparison region, showed no difference between the left and right sides in either group. Severity of thought disorder in the patients was related to asymmetry. CONCLUSIONS: This is a clear demonstration of a reversal of expected symmetry in the brains of right-handed schizophrenic patients, which involves a region of key importance in normal human behavior. The nature of the abnormality strongly suggests that schizophrenia is a neurodevelopmental disorder.

Adult↗

PubMed2001

Adaptation and habituation to an open field and responses to various stressful events in animals with neonatal lesions in the amygdala or ventral hippocampus.

A rat model of neurodevelopmental psychopathological disorders, designed to determine neurodevelopmental deficits following damage to the brain early in life, was used to investigate behavioural changes in adaptation and habituation to an open field and responses to different kinds of stressful events. Animals with bilateral ibotenic acid lesions in the amygdala or ventral hippocampus on day 7 or 21 of life were compared to sham-operated animals. According to the model it was assumed that behavioural changes in animals lesioned on day 7, but not in animals lesioned on day 21 of life, were caused by maldevelopment of one or more structures connected to the damaged area. Animals lesioned in the amygdala or ventral hippocampus on day 7, but not animals lesioned in these structures on day 21 of life, displayed decreased (within-session) adaptation and (between-session) habituation to the open field and a decrease in immobility in the forced swim test, whereas only animals lesioned in the amygdala displayed enhanced general activity. These results were indicative of neurodevelopmental deficits. No changes in stress-induced hyperthermia were found, while animals lesioned in the amygdala both on day 7 or 21 of life exhibited decreased conditioned ultrasonic vocalizations. These latter results suggest that the amygdala is implicated in the conditioned stress-induced response. The contribution of the present findings to the animal model of neurodevelopmental disorders like schizophrenia and possible brain structures and neurotransmitter systems involved in the neurodevelopmental deficits are discussed.

Adaptation, Biological↗

PubMed2000

New research directions in neuroepidemiology.

Many of the risk factors previously identified for disorders such as Alzheimer's disease, periventricular leukomalacia, multiple sclerosis, stroke, cerebral palsy, mental retardation, and acquired learning and attention disorders ultimately may be shown to damage the central and peripheral nervous systems through activation of inflammatory mediators. The challenge to epidemiologists in the future is to expand use of epidemiologic methods to explore how immune-mediated insults produce CNS disorders in human populations. Studies of the association of use of nonsteroidal anti-inflammatory drugs with risk of Alzheimer's disease and those of the association of immune parameters with risk of cerebral palsy are excellent examples of how epidemiology can contribute to our understanding of the causes of neurologic and/or neurodevelopmental disorders. Many of the immune parameters of interest have short half-lives and are difficult to measure outside of the laboratory setting. Questions also remain as to the proper timing of measurements in relation to the initial insult and, in some cases, which tissue is the most appropriate to sample. These measurement issues will need to be resolved before use of immune biomarkers in epidemiologic studies of the etiologies of neurologic disorders can be fully realized. Epidemiologists are most likely to help identify ways to prevent neurologic disorders if they are knowledgeable about the molecular biology of inflammation, modulators of CNS vulnerability, and genetic polymorphisms that influence both inflammation and CNS vulnerability and are prepared to become adept at biomarker epidemiology. This does not necessarily compel them to gain extensive knowledge of neurobiology. Rather, neuroepidemiology in the 21st century will require increased collaboration between epidemiologists, neurologists, and neurobiologists.

Aged↗

PubMed2000

Placental pathology for the surgical pathologist.

Pathologic examination of the placenta is of clinical importance in the evaluation of pregnancies with a less than perfect outcome. Morphologic alterations of the placenta can mirror disorders of the fetus and the mother and evaluation of the placenta can identify clinically significant lesions, allow understanding of a child's disability and may have a role in resolving medical-legal disputes. Pathologic findings in the placenta can provide information on the pathogenesis of cerebral palsy, mental retardation, or neurodevelopmental disorders. This review will cover a variety of frequently encountered, clinically important, and morphologically distinct disorders of the placenta. The current understanding of the clinical implications of lesions for the mother, infant, and for future pregnancies will also be considered.

Adult↗

PubMed2002

Effects of genetic background on neonatal Borna disease virus infection-induced neurodevelopmental damage. II. Neurochemical alterations and responses to pharmacological treatments.

The gene-environment interplay is thought to determine variability in clinical conditions and responses to therapy in human neurodevelopmental disorders. Studying abnormal brain and behavior development in inbred strains of rodents can help in the identification of the complex pathogenic mechanisms of the host-environment interaction. This paper is the second one in a series of the two reports of the use of the Borna disease virus (BDV) infection model of neurodevelopmental damage to characterize effects of genetic background on virus-induced neurodevelopmental damage in inbred rat strains, Lewis and Fisher344. The present data demonstrate that neonatal BDV infection produced regional and strain-related alterations in levels of serotonin, norepinephrine and in levels of serotonin turnover at postnatal day 120. Neonatal BDV infection also induced upregulation of hippocampal 5-HT(1a) and cortical 5-HT(2a) receptors in Lewis rats and downregulation of cortical 5-HT(2a) receptors in Fisher344 rats. BDV-associated regional downregulation of D(2) receptors and dopamine transporter sites were noted in Fisher344 rats. In addition to the neurochemical disturbances, neonatal BDV infection induced differential responses to serotonin compounds. While 8-OH-DPAT suppressed virus-enhanced ambulation in BDV-infected Fisher344, fluoxetine inhibited virus-induced hyperactivity in BDV-infected Lewis rats only. The present data provide new insights into the pathogenic events that lead to differential responses to pharmacological treatments in genetically different animals following exposure to the same environmental challenge.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Antineuronal antibodies: tics and obsessive-compulsive symptoms.

Fluorescent serum antibody determinations were used to examine whether children with obsessive-compulsive disorder (OCD) or less pervasive obsessive-compulsive symptoms (OCS) would show evidence of caudate nucleus involvement. Recent studies of OCD have documented smaller caudate nucleus volumes in adults with childhood onset than in normal controls, but not smaller putamen volumes. Thirty-eight cases were recruited from an ongoing study of childhood neurodevelopmental disorders. Nineteen samples from clinical cases had existing or previously documented OCS and attention-deficit hyperactivity disorder (ADHD) with or without concomitant tics. Nineteen additional clinical controls with ADHD, but without tics or OCS, were identified. The sera from clinical cases showed antibodies directed against caudate [odds ratio (OR) 2.0; 95% confidence interval (CI) 1.0 to 4.1], putamen (OR 3.0; 95% CI 1.5 to 5.8), or both (OR 2.9; 95% CI 1.58 to 5.7) at a rate significantly higher than that of clinical controls, providing evidence of basal ganglia involvement in OCS. These preliminary data do not support a differential effect against caudate compared to putamen for these children, but suggest a more generalized central nervous system response.

Attention Deficit Disorder with Hyperactivity↗

PubMed2006

Evidence for abnormal early development in a mouse model of Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females, associated in most cases to mutations in the MECP2 gene. After an apparently normal prenatal and perinatal period, patients display an arrest in growth and in psychomotor development, with autistic behaviour, hand stereotypies and mental retardation. Despite this classical description, researchers always questioned whether RTT patients did have subtle manifestations soon after birth. This issue was recently brought to light by several studies using different approaches that revealed abnormalities in the early development of RTT patients. Our hypothesis was that, in the mouse models of RTT as in patients, early neurodevelopment might be abnormal, but in a subtle manner, given the first descriptions of these models as initially normal. To address this issue, we performed a postnatal neurodevelopmental study in the Mecp2(tm1.1Bird) mouse. These animals are born healthy, and overt symptoms start to establish a few weeks later, including features of neurological disorder (tremors, hind limb clasping, weight loss). Different maturational parameters and neurological reflexes were analysed in the pre-weaning period in the Mecp2-mutant mice and compared to wild-type littermate controls. We found subtle but significant sex-dependent differences between mutant and wild-type animals, namely a delay in the acquisition of the surface and postural reflexes, and impaired growth maturation. The mutant animals also show altered negative geotaxis and wire suspension behaviours, which may be early manifestations of later neurological symptoms. In the post-weaning period the juvenile mice presented hypoactivity that was probably the result of motor impairments. The early anomalies identified in this model of RTT mimic the early motor abnormalities reported in the RTT patients, making this a good model for the study of the early disease process.

Animals↗

PubMed2006

The neuropsychiatry of Niemann-Pick type C disease in adulthood.

Psychotic symptoms occur in a variety of medical and neurological conditions. The authors describe three young men with a variant form of Niemann-Pick type C disease, a neurodegenerative disorder related to abnormal intracellular cholesterol metabolism, who presented with psychosis in early adulthood. Two patients were treated for schizophrenia for many years prior to a diagnosis of Niemann-Pick type C. The cases presented in this article illustrate the role of changes in both white and gray matter structures in psychosis, and, like the assessments of other neurodevelopmental disorders that predispose toward psychotic presentations, shed light on the underlying pathophysiology of major mental disorders.

Adult↗

PubMed2026

Evidence supporting the role of GIGYF2 in synapse development and autism.

Autism spectrum disorder (ASD) is a heterogeneous condition in which genetically defined subtypes offered insights into underlying biological mechanisms and potential targeted treatments. Here, we investigate the clinical and pathogenic significance of GIGYF2 variants in ASD through an integrated approach combining clinical genetics, conditional knockout (cKO) mouse models, neurobiology, and molecular studies. Through targeted sequencing, large-scale genomic data analysis of neurodevelopmental disorder cohorts, and international collaborations, we identified ten affected individuals from eight families harboring de novo or dominantly inherited likely gene-disruptive (LGD) variants and 13 affected individuals from 13 families with de novo missense variants in GIGYF2. Clinical characterization of 16 probands with GIGYF2 variants revealed common features, including ASD, language problems, intellectual disability, and anxiety. In a Gigyf2 cKO mouse model, we observed pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in affected individuals. Mechanistically, Gigyf2 deficiency disrupted synaptic homeostasis, as evidenced by altered spine density and miniature excitatory postsynaptic currents, and impaired IGF-1R/mTOR signaling, along with dysregulation of synapse-related genes such as Nrp2. Pharmacological inhibition of mTOR with rapamycin or Torin1, as well as Nrp2 knockdown rescued synaptic defects in Gigyf2 KO neurons. These findings define a novel ASD subtype associated with GIGYF2 variants and establish GIGYF2 as a key regulator of synaptic development and function, implicating GIGYF2 dysfunction in ASD pathogenesis and highlighting the IGF-1R/mTOR pathway as a potential therapeutic target for GIGYF2-related ASD subtype.

Journal Article↗

PubMed2026

Altered ECM deposition and cell adhesion signaling in a human cortical organoid model of fragile X syndrome.

Fragile X Syndrome (FXS) is the most common inherited intellectual disability, and the most common monogenic cause of autism spectrum disorder (ASD). It is caused by epigenetic silencing of the FMR1 gene leading to the loss of FMRP, an RNA-binding protein that regulates local mRNA translation in neuronal dendrites, crucial for synapse development. Three-dimensional (3D) brain organoid models derived through in vitro differentiation of pluripotent stem cells offer a powerful tool to dissect the underlying mechanisms of neurodevelopmental disorders. Here, we generated human FXS and control organoids using isogenic human embryonic stem cell clones with and without the FXS mutation. Our results show that mature FXS cortical brain organoids can be derived by inhibiting the TGFβ and Wnt pathways. Moreover, expression analyses including immunofluorescence, qRT-PCR, proteomics and western blotting reveal altered levels of neuronal markers and ECM deposition along with modulated downstream signaling molecules. Interestingly, in silico analysis of proteomics revealed several altered pathways, such as cell adhesion, regulation of neurogenesis and cell cycle that are implicated in FXS. Collectively, our unique FXS-organoids derived from isogenic hESC lines may serve as a model for studying the pathology of FXS disorder and for developing therapeutical intervention.

Humans↗

PubMed1991

Neurocognitive disorders in psychiatry: a case example of diagnostic and treatment dilemmas.

We present a case example that illustrates the diagnostic and treatment difficulties engendered by adult psychiatric patients with primary behavioral problems and neurocognitive disorders. In the case cited, the neuropsychological evaluation plays a significant role in reconceptualizing a patient who had accrued multiple psychiatric diagnoses including schizophrenia, borderline personality, and impulse control disorder. Formal examination revealed deficits in language, executive, and attentional functions that were far greater than had been expected and led to a major change in treatment strategy, including successful trial of imipramine and nadolol and more structured milieu therapy. The cognitive deficit and intrapsychic conflict models are used to demonstrate the critical aspects of our diagnostic reclassification of the patient to Neurodevelopmental Disorder of Unknown Etiology and Auditory Attention Deficit Disorder.

Adult↗

PubMed2003

[Clinical features of epilepsy in autism spectrum disorders].

Autism is a rare disease, but is currently in vogue. An incidence of 1/1,000 has been estimated for early childhood autism, but in autism spectrum the incidence can reach 30/1,000. The clinical characteristics of autism are cognitive language disorders, lack of social interaction, obsessive behaviours with stereotypic movements and epilepsy. For some authors it is an associated symptom while for others it is a cardinal symptom of the disease. Epilepsy in autism, as an association, was reported as early as 1944 by Leo Kanner, in describing his initial work involving 11 cases and how one of them suffered from epilepsy. In 1960, the prevalence of epilepsy among autistic patients was evaluated and found to be much higher than in the normal population. The figures differ from author to author, but really they depend on age: the higher the age, the greater the prevalence of epilepsy. It was in fact this detail that drew our attention to this issue, and triggered the first questions in our research into autism and epilepsy. The series vary from 4 to 86%, depending on the methodology used to confirm the epilepsy. In our casuistics, between the ages of 1 and 18 years, 20% of these children with autism spectrum disorders suffer some kind of epileptic seizures, and 80% suffer what other researchers call subclinical seizures . In this paper, the symptomatology of the most important subclinical seizures that have been observed in these children is presented; the diseases associated with autism are commented on; the concept of primary and secondary autism is discussed; we explain why seizures occur in autism and their consequences as a neurodevelopmental disorder, and we put forward an interesting hypothesis within our general theory of autism. We also comment on the importance that the use of functional magnetic images in the study of autism has in our research.

Adolescent↗

PubMed2026

When Neurodevelopment Meets Autoimmunity: Pemphigus Foliaceus in Rett Syndrome Expands the Clinical Spectrum-A Case Report.

Rett syndrome (RTT, OMIM 312750) is a complex multisystem neurodevelopmental disorder. Evidence suggests that RTT may have an autoimmune component and inflammatory activation. However, the autoimmune manifestations remain poorly described. Pemphigus foliaceus is a debilitating autoimmune blistering condition caused by IgG autoantibodies that target desmoglein-1 (Dsg1), resulting in widespread skin blistering and lesions. We report a case of pemphigus foliaceus in a 20-year-old female with RTT and discuss its clinical implications. Clinical data obtained from electronic health records were extracted and reviewed. Genetic testing was performed to identify the specific methyl-CpG-binding protein 2 (MECP2) mutation and on an expanded panel of 55 genes associated with pemphigus foliaceus and related blistering disorders. The individual had pemphigus foliaceus, which required immunosuppression, intravenous immunoglobulin (IVIg) therapy, and Rituximab. The disease trajectory was complicated by infections, aspiration pneumonia, and hypoxic cardiac arrest. There was progressive functional decline, and disease control was difficult to achieve, with frequent flares. Genetic testing confirmed a heterozygous pathogenic MECP2 variant (NM_001110792.1:c.952C>T; p.(Arg318Cys)). HLA genotyping identified alleles consistent with the HLA-DRB1*04:02-HLA-DQA1*03:01-HLA-DQB1*03:02 (DR4/DQ8) haplotype. Furthermore, genetic analysis identified a heterozygous DSG1 variant rs12967407. This study reports the first case of pemphigus foliaceus in RTT, expanding the clinical spectrum of RTT beyond its neurodevelopmental phenotype. The DR4/DQ8 haplotype, previously associated with pemphigus susceptibility, supports a background of genetic susceptibility in this individual. No causal association between RTT and pemphigus foliaceus can be inferred from this single case. Rather, this case demonstrates that a rare autoimmune disorder such as pemphigus foliaceus can co-occur with a pathogenic MECP2 mutation. The coexistence of a genetic and autoimmune disease can result in a more complex clinical presentation and treatment course. The case further emphasises the need for increased vigilance in identifying new and emerging systemic pathology alongside RTT.

Humans↗

PubMed1995

An automated electronic method for quantifying spinning (circling) in children with autistic disorder.

This pilot study examined and quantified rotational asymmetry (the tendency to turn preferentially to the right or left side). An automated device was used to measure turning (circling) in 9 children with autism and 27 normal control subjects and confirmed clinical observations of stereotypical spinning behavior in patients with autism. This behavior was significantly preferential toward the left side relative to control subjects (P = 0.0009, two-tailed). Group membership accounted for approximately 40% of variance. Although the precise causes of autism are not known, these preliminary data suggest that the spinning behavior often seen in children with neurodevelopmental disorders can be reliably measured. Furthermore, spinning in autism may most often manifest as specific right-hemispace neglect.

Arousal↗

PubMed2005

Language cannot be reduced to biology: perspectives from neuro-developmental disorders affecting language learning.

The study of language knowledge guided by a purely biological perspective prioritizes the study of syntax. The essential process of syntax is recursion--the ability to generate an infinite array of expressions from a limited set of elements. Researchers working within the biological perspective argue that this ability is possible only because of an innately specified genetic makeup that is specific to human beings. Such a view of language knowledge may be fully justified in discussions on biolinguistics, and in evolutionary biology. However, it is grossly inadequate in understanding language-learning problems, particularly those experienced by children with neurodevelopmental disorders such as developmental dyslexia, Williams syndrome, specific language impairment and autism spectrum disorders. Specifically, syntax-centered definitions of language knowledge completely ignore certain crucial aspects of language learning and use, namely, that language is embedded in a social context; that the role of envrironmental triggering as a learning mechanism is grossly underestimated; that a considerable extent of visuo-spatial information accompanies speech in day-to-day communication; that the developmental process itself lies at the heart of knowledge acquisition; and that there is a tremendous variation in the orthographic systems associated with different languages. All these (socio-cultural) factors can influence the rate and quality of spoken and written language acquisition resulting in much variation in phenotypes associated with disorders known to have a genetic component. Delineation of such phenotypic variability requires inputs from varied disciplines such as neurobiology, neuropsychology, linguistics and communication disorders. In this paper, I discuss published research that questions cognitive modularity and emphasises the role of the environment for understanding linguistic capabilities of children with neuro-developmental disorders. The discussion pertains to two specific disorders, developmental dyslexia and Williams syndrome.

Genotype↗

PubMed1995

Rett syndrome studies of natural history and search for a genetic marker.

The commonly held notion that Rett syndrome (RS) is a neurodegenerative disorder with normal early development was examined by an epidemiological survey and review of medical records and serial neurological and development evaluations. In some subjects, deviance from normal development was evident from the perinatal period, and gradually became more prominent with age. These findings are convincing when seen in conjunction with a reduction in velocity of brain growth, as early as 2-4 months of life, well before the recognition of gross neurological deficits. Neurodevelopmental evaluations provide no indication that there is progressive loss of adaptive behaviors, or communication skills to indicate a neurodegenerative process. Taken together with the known neuropathological and neurochemical changes in RS brain we hypothesize that RS is a neurodevelopmental disorder, which has a genetic basis, and affects subsets of neurons and their connections during a period of vigorous brain growth, when synapse formation and pruning are at a peak. Studies of mitochondrial (mt) DNA in brain to understand the genetic mechanisms underlying matrilineal inheritance in the few familial cases, and mt structural and enzyme deficiencies have been unrevealing to date.

Adolescent↗

PubMed2000

Neurobiology of schizophrenia.

Schizophrenia is a common chronic and disabling brain disease of unknown etiology, pathogenesis, and mechanism. Whether schizophrenia represents a single disorder of markedly variable expression or a family of clinically related disorders is unclear. Genetic factors, most likely multiple genes of modest effect, play a major role in its etiology, but an environmental "second hit" may be necessary for clinical expression. The inherited biological susceptibility to schizophrenia is probably expressed clinically as nonpsychotic abnormal personality traits, plus numerous biological markers (cognitive, anatomical, and psychophysiological) that are all found significantly more commonly in the population than is schizophrenia. Neuropathological studies suggest that schizophrenia may be a neurodevelopmental disorder, characterized by reduced neuropil, with no evidence for ongoing cell death. A hypothesized mechanism for these changes involves cell migrational abnormalities occurring in the fetal brain. Schizophrenia is also distinguished by biochemical abnormalities involving the dopamine, GABA, and glutamate systems, and NMDA and nicotinic receptors. Structural and functional brain imaging studies suggest both global and regional abnormalities as well as "disconnections" of specific cerebral circuits. Despite the lack of knowledge regarding pathophysiology, there are reasonably effective treatments for schizophrenia. As the neurobiology of the disorder is unraveled, more effective, targeted treatments will become available.

Humans↗