Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment.

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events

Magnetic resonance imaging study of corpus callosum abnormalities in patients with different subtypes of schizophrenia

Background. Reductions in the size of the corpus callosum (CC) have been described for schizophrenia patients, but little is known about the possible regional differences in schizophrenia subtypes (paranoid, disorganised, undifferentiated, residual).  Methods. We recruited 58 chronically schizophrenic patients with different subtypes, and 31 age-and-gender matched healthy controls. The callosum was extracted from a midsagittal slice from T1 weighted magnetic resonance images, and areas of the total CC, its five subregions, CC length and total brain volume were compared between schizophrenia subtypes and controls. Five subregions were approximately matched to fibre pathways from cortical regions.  Results. Schizophrenia patients had reduced CC total area and length when compared with controls. Disorganised and undifferentiated schizophrenics had a smaller prefrontal area, while there was no significant difference for the paranoid and residual groups. The premotor/supplementary motor area was smaller in all schizophrenia subtypes. The motor area was smaller only in the disorganised group. A smaller sensory area was found in all subtypes except the residual group. Parietal, temporal and occipital areas were smaller in the paranoid and undifferentiated groups. Total brain volume was smaller in all schizophrenia subtypes compared with controls, but did not reach statistical significance.  Conclusion. These findings suggest that the heterogeneity of symptoms may lead to the different CC morphological characteristics in schizophrenia subtypes

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Use of Dysmorphology for Subgroup Classification on Autism Spectrum Disorder in Chinese Children

Data from 1,261 Chinese Autistic Spectrum Disorder (ASD) patients were evaluated and categorized into dysmorphic (10.79 %) and non-dysmorphic groups (89.21 %) upon physical examination by the presence of dysmorphic features. Abnormal MRI/CT result, IQ scores and epilepsy were significantly associated with the dysmorphic group of ASD children. However, gender, EEG abnormality and family history and recurrence of ASD were not found to be significantly different between group statuses. It is suggested that results collected from the Chinese population generally resembles that found in the Caucasians with ethnical differences still present. Current study supports the result shown in Miles' study (Miles et al. in Am J Med Genet 135A:171-180, 2005), in which heterogeneity subtypes of autism of different genetic origins which could be distinguished by presence of dysmorphic features on the patients.postprin

Investigating the role of the transcriptional coregulator Cited2 in regulating intermediate progenitor proliferation and modulating behavior

The mammalian neocortex develops from a thin layer of neuroepithelial cells into a robust mosaic of differentiated neurons organized into distinct layers and functional areas. This process requires a complex choreography of transcription factors and epigenetic regulators to be spatially and temporally activated in a precise manner. Disruptions in any aspect of this delicate process may lead to neurodevelopmental disorders like autism spectrum disorder, schizophrenia, or intellectual disability. One such transcriptional coregulator that is a crucial regulator of neocortical development is Cited2. Previous work demonstrated that forebrain-specific Cited2 loss-of-function causes a reduction in neocortical progenitor proliferation which leads to reduced thickness of neocortical superficial layers, reduced neocortical length, and a reduction of interhemispheric connectivity throughout the neocortex. This dissertation elucidates the molecular mechanism by which CITED2 functions in the developing neocortex. Further, I explore the effects Cited2 cKO has on early post-natal and young adult behaviors and reveal disruptions in neonatal ultrasonic vocalizations, increased rearing behavior, and increased sensitization to repeated acoustic startle. Additionally, I perform transcriptome analysis of purified intermediate progenitor cells (IPCs) from Cited2 cKO and WT neocortices to elucidate affected biological processes that underpin the disrupted neocortical development and behavior of Cited2 cKO mice. I uncover novel deficits in primary cilia function and potential premature neurogenesis. Further, we investigate the role CITED2 plays in neuronal fate decisions of Layer V projection neurons, exploring the relationship between Cited2 and a recently discovered microRNA posited to modulate Cited2 expression. Finally, I delve into maternal diet alteration and show folic acid supplementation rescues morphological phenotypes generated by Cited2 cKO. In summary, we identify the Cited2 forebrain-specific knockout as an excellent novel system to study mechanisms underpinning neurodevelopment and the etiology of neurodevelopmental disorders

Puzzle Pieces: Neural Structure and Function in Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a behavioural phenotype encompassing hyperphagia, intellectual disability, social and behavioural difficulties, and propensity to psychiatric illness. Research has tended to focus on the cognitive and behavioural investigation of these features, and, with the exception of eating behaviour, the neural physiology is currently less well understood. A systematic review was undertaken to explore findings relating to neural structure and function in PWS, using search terms designed to encompass all published articles concerning both in vivo and post-mortem studies of neural structure and function in PWS. This supported the general paucity of research in this area, with many articles reporting case studies and qualitative descriptions or focusing solely on the overeating behaviour, although a number of systematic investigations were also identified. Research to date implicates a combination of subcortical and higher order structures in PWS, including those involved in processing reward, motivation, affect and higher order cognitive functions, with both anatomical and functional investigations indicating abnormalities. It appears likely that PWS involves aberrant activity across distributed neural networks. The characterisation of neural structure and function warrants both replication and further systematic study

Roles of autism gene ARID1B in murine brain development and behavior

Autism spectrum disorder (ASD) and intellectual disability (ID) are highly prevalent neurodevelopmental disorders characterized by social and communication deficits, stereotyped behaviors, cognitive dysfunction, and deficits in adaptive behaviors. The pathogenesis underlying these disorders remains unknown, and thus no pharmacologic or genetic therapies are currently available. Recent progress in the field has shown that haploinsufficiency of the AT-rich interactive domain-containing 1B (ARID1B) gene is a genetic cause of ASD and ID. Our lab recently developed an Arid1b knockout mouse model to better study its role in the pathogenesis of these disorders. One theory regarding the cause of neurodevelopmental disorders is disruption of the excitatory/inhibitory balance in the brain. We previously showed that interneuron deficits lead to an excitatory/inhibitory imbalance in Arid1b knockout mice, playing a significant role in the observed behavioral phenotypes. Interneurons are highly heterogenous cell types in the brain; however, little is known regarding how the different subtypes modulate various behaviors. In chapter 2, we dissect the individual roles of the two most populous interneurons in the cerebral cortex, parvalbumin and somatostatin subtypes, in ASD/ID behaviors seen with ARID1B haploinsufficiency. We show that parvalbumin interneurons affect social and emotional behaviors, while somatostatin interneurons primarily affect stereotyped behaviors and cognitive function. In addition to interneuron deficits, several studies have also implicated altered neurite outgrowth of cortical projection neurons in ASD and ID. Furthermore, deficits in neurotrophic signaling, a master regulator of neurite outgrowth, is also frequently observed. In chapter 3, we examine a potential role of ARID1B in regulating neurite development of excitatory neurons during corticogenesis. We show that loss of the Arid1b gene leads to disrupted neurite outgrowth and altered development of the corpus callosum. Additionally, we suggest a likely role of ARID1B in the BDNF neurotrophic signaling pathway. Together, these studies provide insight into possible roles of ARID1B during neurogenesis, shedding further insight into the pathogenesis of ASD and ID

Development, specification, and diversity of callosal projection neurons

Callosal projection neurons (CPN) are a diverse population of neocortical projection neurons that connect the two hemispheres of the cerebral cortex via the corpus callosum. They play key roles in high-level associative connectivity, and have been implicated in cognitive syndromes of high-level associative dysfunction, such as autism spectrum disorders. CPN evolved relatively recently compared to other cortical neuron populations, and have undergone disproportionately large expansion from mouse to human. While much is known about the anatomical trajectory of developing CPN axons, and progress has been made in identifying cellular and molecular controls over midline crossing, only recently have molecular-genetic controls been identified that specify CPN populations, and help define CPN subpopulations. In this review, we discuss development, diversity, and evolution of CPN.Stem Cell and Regenerative Biolog