Genetics Of Childhood Disorders Research Articles

Genetics of Childhood Disorders: LV. Prenatal Drug Exposure

The topic of the reviews in this series will be prenatal exposure to drugs such as cocaine and alcohol and their effects on neural ontogeny and associated neurocognitive/neurobehavioral development in offspring. Exposure to drugs prenatally, surely an important concern for practitioners, is part of the broader field of behavioral teratology or the study of perinatal developmental injury and of the factors—including drug and toxin exposure, parental disease or impairment, and birth accidents—that increase the risk of immediate or later physical injury or developmental impairment.

Genetics of Childhood Disorders: LIV. Learning and Memory, Part 7: Maintenance of Long-Term Potentiation

Before moving on to the processes that contribute to the persistence of long-term potentiation (LTP), we need to address an apparently straightforward issue: which side of the synapse expresses LTP? We have seen that the main events of LTP induction occur in postsynaptic signaling pathways. Does this mean that the locus of LTP expression is also postsynaptic? At the CA3–CA1 synapse, the preponderance of electrophysiological evidence favors the postsynaptic side of the synapse, but this has been a contentious area of research and some data support the hypothesis of increased transmitter release in LTP. The problem of the site of LTP expression has been approached using several different strategies. One method is to determine the rate of glutamate release. The efflux of glutamate from a hippocampal slice can be directly measured, and early work showed an elevation during LTP. However, synaptic release represents only a fraction of total glutamate efflux, and metabolic changes could be largely responsible for the observed increases. A more sophisticated experimental approach exploits the active uptake of synaptic glutamate by glial cells, resulting in graded glial transporter currents that can be recorded. These currents are not increased during LTP, suggesting that the locus of the potentiation is postsynaptic. The hypothesis that LTP expression is restricted to the postsynaptic cell has been challenged by experiments in which vesicle recycling at the CA3–CA1 synapse was monitored using the presynaptic loading of a fluorescent dye. An increase in vesicle recycling would indicate that glutamate-containing vesicles were being turned over at a higher rate, presumably due to increased synaptic release. Such an effect occurred following LTP-inducing stimulation, supporting a presynaptic contribution to the expression of LTP. A second approach to identifying the locus of LTP exploits the voltage-dependent block of N-methyl-D-aspartate (NMDA) receptors described in the previous column, a property that is not shared by (AMPA)-type receptors. This difference can be used to separate the synaptic response into AMPA and NMDA components because the contribution of the NMDA-mediated current will depend upon the postsynaptic membrane voltage. If an increase in glutamate release is responsible for LTP, then the AMPA and NMDA receptor-mediated responses should increase equally. But most studies show that only the AMPA component is potentiated during LTP, consistent with a postsynaptic change that is restricted to AMPA receptors.

Genetics of Childhood Disorders: LIII. Learning and Memory, Part 6: Induction of Long-Term Potentiation

The last several columns have discussed the organization of human memory. The discovery of different types of memory has come from studies of human neurological patients with deficits in some forms of memory while others are preserved. For example, the memory for a particular motor skill or the ability to learn a new motor task may persist even though an individual has lost the ability to learn new faces, names, or recent events. A particularly striking example of this is the case of H.M., perhaps the most well-studied individual in the field of learning and memory. H.M. fell from a bicycle as a child and developed intractable seizures as an adolescent. In an effort to control his seizures, bilateral resections were made of his hippocampus and the medial aspect of his temporal lobes. Although his seizures abated, H.M. lost the ability to remember new information for more than a few minutes. However, H.M. was still capable of learning new motor tasks. As a result of these studies, neurobiologists came to the conclusion that the hippocampus is critically involved in translating short-term memories into long-term memories. A tremendous amount of research has been devoted to understanding the underlying molecular mechanisms that are responsible for this ability. A prominent characteristic of synapses is their capacity for plasticity, reflected as increases or decreases in the efficiency of transmission. For nearly three decades, the effort to understand how synapses encode memories has focused mainly on one form of synaptic plasticity, long-term potentiation (LTP), with the majority of studies being conducted in the hippocampus. The persistent increase in synaptic strength observed in LTP has several characteristics that one would expect of a fundamental mnemonic process. Before we look at an example of an experiment that examines LTP, we will review the neuroanatomy of the hippocampus. The hippocampus is a C-shaped structure that is tucked beneath the neocortex. It has a relatively simplified architecture and is called the archicortex to distinguish it from the more complex laminated structure found in the neocortex. The hippocampus is divided into two major parts: the dentate gyrus and the CA fields. CA stands for “cornu ammonis” or “Ammon’s horn.” The cells within the dentate gyrus are called granule cells and form a single layer of cells, whereas those of the CA fields are pyramidal neurons that also form a single monolayer. The neuronal circuitry of the hippocampus is characterized by a trisynaptic pathway (Fig. 1A), with glutamate serving as the neurotransmitter at all three synapses. The first set of synapses is made by the incoming projections that originate in the entorhinal cortex and provide excitatory synaptic inputs to the granule cells in the dentate gyrus (perforant pathway). The granule cells then send their projecting, excitatory axons (mossy fibers) to make the second synaptic connections on the dendritic arbors of pyramidal neurons of the CA3 subregion. The CA3 neurons in turn send one branch of their excitatory projections to the pyramidal neurons of the CA1 subfield (Schaffer collaterals). There are several reasons why this region is the most heav

Genetics of Childhood Disorders: LII. Learning and Memory, Part 5: Human Cognitive Disorders and the ras/ERK/CREB Pathway

Genetics of Childhood Disorders: LII. Learning and Memory, Part 5: Human Cognitive Disorders and the ras/ERK/CREB Pathway

Genetics of Childhood Disorders: LI. Learning and Memory, Part 4: Human Cognitive Disorders and the ras/ERK/CREB Pathway

It is difficult to overstate the likely impact of recent advances in mammalian genetic engineering. The ability to engineer the mammalian genome will eventually rank along with splitting the atom, developing the computer, and inventing the printing press in its impact on the human condition. If taken to its limits, genetic engineering could allow us to restructure ourselves at the molecular level—a thought both ethically sobering and medically promising.

Genetics of Childhood Disorders: L. Learning and Memory, Part 3: Fear Conditioning

Described initially at the beginning of the 20th century by Ivan Pavlov, classical conditioning involves the pairing of neutral stimuli with aversive or appetitive cues. This results in learning. Formally neutral stimuli now predict salient events. One form of Pavlovian conditioning is fear conditioning, the primary associative learning mechanism involved in aversive emotional learning. It is through this process that we learn to be fearful of people, animals, objects, and places. From a psychological perspective, it is one of best understood types of learning in mammals because the stimulus and response properties can be very carefully controlled. For these reasons, Pavlovian fear conditioning has served as a powerful animal model of fear and anxiety disorders including phobia, panic disorder, post‐traumatic stress disorder, and possibly many of the “neurotic” associations of everyday life. If we can understand the underlying molecular basis for how a previously innocuous stimulus leads to intense fear in an animal model, the hope is that such an understanding will eventually lead to better treatments in humans disabled by these crippling disorders.

Genetics of Childhood Disorders: XLIX. Learning and Memory, Part 2: Multiple Memory Systems

Memory is a broad topic that has its roots in both biology and psychology. Many of the important questions about memory concern structure, organization, and function and must be addressed at a relatively global, systems level of analysis. Two long-standing and interrelated questions of this kind have been of central interest. The first is whether there is more than one kind of memory. The second concerns what brain structures and pathways are important for memory. Scientific work directed at these questions has introduced the terms declarative memory and nondeclarative memory to neuroscience and identified a number of parallels between the neural organization of memory in humans and other animals.

Genetics of Childhood Disorders: XLVIII. Learning and Memory, Part 1: Fragile X Syndrome Update

Journal of the American Academy of Child & Adolescent Psychiatry - Vol. 42 - N° 3 - p. 372-375

Genetics of Childhood Disorders: XLVII. Autism, Part 6: Duplication and Inherited Susceptibility of Chromosome 15q11-q13 Genes in Autism

253Autism is a neuropsychiatric disorder that exhibits high heri-tability and is considered to have a complex genetic etiology. Asibling of a child with autism has a 25 to 50 times greater riskfor developing autism than someone in the general population.Autism displays both clinical and genetic heterogeneity, as reviewedin last month’s column. A different set of genes may confer riskin different families or individuals (genetic heterogeneity), anddifferent siblings in a given family may have a different clinical

Genetics of Childhood Disorders: XLVI. Autism, Part 5: Genetics of Autism

Autism is one of the most heritable complex genetic disorders in psychiatry. Despite this high heritability, autism has a heterogeneous etiology, with multiple genes and chromosomal regions likely to be involved. Scientists are using both indirect and direct approaches to identify autism susceptibility genes. Indirect approaches include the characterization of less complex genetic disorders that share some of the symptoms of autism, including Rett syndrome or fragile X syndrome, in the hope that these analyses will provide clues to the more complex disorder of autism (see recent reviews in this space, February and May 2000). Direct approaches include three overlapping methodologies to identify genes or regions of interest in autism: chromosomal methods, such as karyotyping and fluorescence in situ hybridization (FISH); linkage studies, such as genome screens in affected sibling pairs; and gene association studies, including candidate gene studies. These approaches are yielding preliminary findings that are reviewed here. While no specific gene variant has been identified and confirmed that contributes to the expression of autism, it is very likely that several will be confirmed over the next decade.

Genetics of Childhood Disorders: XLV. Autism, Part 4: Serotonin in Autism

Early experiments on the isolation and identification of serotonin (5-hydroxytryptamine, 5-HT) were carried out from the late 1930s through the early 1950s. These studies demonstrated the presence of 5-HT in blood and in enterochromaffin cells of the gut, and they established the indole structure of the molecule. In 1953, it was shown that the mammalian brain contained appreciable (μg/g) quantities of 5-HT. A consideration of 5-HT's actions as a vasoconstrictor and cardiostimulant, the parallels between 5-HT and the then-nascent neurotransmitters norepinephrine and acetylcholine, and commonalities with the molecular structure of lysergic acid led rapidly to suggestions that 5-HT might play a role in mental disorders. In 1961, Shain and Freedman reported finding elevated levels of platelet 5-HT in individuals with autism. Serious consideration of the role of 5-HT in autism dates from this time.

Genetics of Childhood Disorders: XLIII. Autism, Part 2: Neural Foundations

Autism is a severe developmental disorder marked by significant impairments in social, behavioral, and communicative functioning. Its early onset, symptom profile, and chronicity strongly argue for a biological basis, and in fact, several of lines of research implicate core biological mechanisms. For example, autism is one of the most strongly genetic conditions, and preliminary linkage data have already identified susceptibility regions likely to contain genes involved in the condition. About a quarter of individuals with autism exhibit a seizure disorder, and a larger number of individuals have abnormal EEGs, which typically indicate bilateral abnormalities without a consistent focus. However, the absence of consistent biological markers presents across all cases and the pronounced heterogeneity of the manifestations of autism have slowed research into its pathophysiology. And yet, major progress is being accomplished following the advent of new tools of biobehavioral research. Novel neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) are beginning to map out the neural systems affected by autism. These include brain areas responsible for emotional and social functions, per

Genetics of Childhood Disorders: XLII. Autism, Part 1: Diagnosis and Assessment in Autistic Spectrum Disorders

Genetics of Childhood Disorders: XLII. Autism, Part 1: Diagnosis and Assessment in Autistic Spectrum Disorders

Genetics of Childhood Disorders: XLI. Stem Cell Research, Part 5: Ethical Questions

Genetics of Childhood Disorders: XLI. Stem Cell Research, Part 5: Ethical Questions

Genetics of Childhood Disorders: XL. Stem Cell Research, Part 4: Neural Horticulture

A fundamental scientific principle held for the past 100 years is that children are born with all the neurons they will ever have. New discoveries in stem cell biology and developmental neuroscience are challenging this idea. Because stem cells are selfrenewing and unspecialized, they can generate many different cell types. Neuronal stem cells are found within germinal centers in the adult brain such as the subventricular zone and the dentate gyrus of the hippocampus. Scientists have discovered how to harvest these cells from early embryos or the adult CNS for further cultivation in vitro. A variety of genetic, environmental, and molecular factors can then be studied to determine whether they influence the types of cells produced and whether they grow into neurons, heart, muscle, or other cell types. At present, many of the critical factors that regulate their eventual fates are poorly understood. However, new evidence suggests that genomic repair is one of the critical determinants for maintaining stem cells and mature neurons throughout life. This column reviews studies of the role of genomic repair in embryonic and stem cell neurogenesis and differentiation. Although the interplay between genes and the environment is well established, recent research has found that physical activity can have a striking effect on neurogenesis, neuronal survival, and differentiation in the mature brain. In several studies, voluntary exercise on a running wheel was found to stimulate proliferation of neuronal stem cells in adult rodent dentate gyrus. Physical activity may increase the production of growth factors and other molecules important for neural development. Combinations of several different growth factors have been used successfully to generate dopamineor serotonin-producing neurons from embryonic stem cells in tissue culture. Once these cells have been propagated and partially differentiated, they may be transplanted into the brain for further study. This type of experiment has been successfully used to treat mice with neurodegenerative disorders of the spinal cord and other brain regions. Scientists have also made the startling discovery that stem cells are present in the adult body that have the capacity to differentiate into a range of cell types, including blood cells or neurons. Stem cells are not committed to a specific function, Genetics of Childhood Disorders: XL. Stem Cell Research, Part 4: Neural Horticulture

Genetics of Childhood Disorders: XXXIX. Stem Cell Research, Part 3: Regulation of Neurogenesis by Stress and Antidepressant Treatment

Mood disorders continue to be major medical problems that affect up to 17% of the population at some point in life and can result in loss of life. Although effective treatments exist, not all patients respond to available medications and there is a time lag of weeks to months in the therapeutic response to antidepressants. The pathophysiology underlying mood disorders has not been identified. Recent advances in neurobiology provide a new conceptual framework for investigating both the pathophysiology and the treatment of mood disorders.

Genetics of Childhood Disorders: XXXVIII. Stem Cell Research, Part 2: Reconstructing the Brain

An unexpected form of plasticity in the adult brain is the constant generation of new neurons throughout adult life. The addition of thousands of new neurons each day may be a means of sculpting brain circuitry. This turnover has important implications not only for brain function but also for brain repair and pathological conditions such as tumors. This review will cover neurogenesis and the identity of stem cells in the adult brain. The adult brain contains two main types of cells, neurons and macroglia. Macroglia comprise oligodendrocytes and astrocytes. Oligodendrocytes are the cells that form myelin sheaths around the axons of neurons and allow the rapid conduction of electrical impulses. Astrocytes are mysterious cells that have multiple functions, including maintaining homeostasis, absorbing neurotransmitters released by neurons, and providing trophic support. Astrocytes are also induced to divide in response to lesions of the brain resulting in the formation of glial scars. Almost all neurons and glia in the brain are derived from multipotent stem cells located in the germinal layers next to the ventricular cavities of the developing brain. As development proceeds, precursors become progressively more restricted

Genetics of Childhood Disorders: XXXVII. News Flash: A Gene for Expressive Language

The ability to speak is uniquely human. Although other species are capable of communicating with each other, the use of speech is a distinguishing feature of Homo sapiens. Is it possible that this trait is determined by specific genes? This question has been debated by linguists for many decades, and both sides of the argument have vocal supporters. The recent isolation of a gene that appears to be critical for the normal acquisition of language is a remarkable achievement and important to clinicians and researchers alike.

Genetics of Childhood Disorders: XXXVI. Stem Cell Research, Part 1: New Neurons in the Adult Brain

Until recently, it was assumed that neurogenesis, or the production of new neurons, occurs only during development and never in the adult organism. The famous neuroanatomist Cajal stated that “Once development was ended, the fonts of growth and regeneration of the axons and dendrites dried up irrevocably. In adult centers, the nerve paths are something fixed and immutable: everything may die, nothing may be regenerated.” This statement holds true for most of the regions of the adult brain. However, there are two adult brain areas in which neurogenesis is observed: the subventricular zone of the anterior lateral ventricles gives rise to cells that become neurons in the olfactory bulb, and the subgranular zone in the dentate gyrus generates new granule cell neurons in the hippocampus, a brain region that is important for learning and memory. The initial studies that suggested that the adult brain could generate new neurons were largely ignored. In the 1960s Joseph Altman and coworkers published a series of papers reporting that some dividing cells in the adult brain survived and differentiated into cells with morphology similar to neurons. They used tritiated thymidine autoradiography to label the cells. Tritiated thymidine is incorporated into the DNA of dividing cells. They found that the highest density of labeling was in the subventricular zone and in the dentate gyrus of the hippocampus. It was known that the dentate gyrus of the hippocampus is essentially devoid of glia. Therefore, Altman attributed the labeling in this region to the uptake of thymidine by dentate granule cells. However, he could not prove that the adult-generated cells were neurons rather than glia, since no phenotypic markers were available that could be used in conjunction with thymidine autoradiography. The absence of specific markers for neurons and glia and continued skepticism surrounding the novel concept of adult neurogenesis limited further development of the research. In the mid 1970s and the early 1980s, Michael Kaplan and his colleagues reexamined the initial observations using the electron microscope and added substantial confidence that neurogenesis could occur in the adult brain. Combining electron microscopy and tritiated thymidine labeling, they showed that

Genetics of Childhood Disorders: XXXIV. Autoimmune Disorders, Part 7: D8/17 Reactivity as an Immunological Marker of Susceptibility to Neuropsychiatric Disorders

Sydenham chorea (SC), a major manifestation of rheumatic fever (RF), is thought to occur when antibodies directed against group A streptococcus (GAS) cross-react with epitopes on neurons of the basal ganglia. In earlier work with SC, Swedo and colleagues identified children who, in addition to chorea, presented with obsessive-compulsive behavior. A precipitous onset of childhood obsessive-compulsive disorder (OCD) after streptococcal pharyngitis was subsequently described that shared many similarities to SC but did not have chorea or clinical signs of RF such as arthritis and carditis. Swedo and colleagues termed this subtype of childhood-onset OCD, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).