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Biomedical subjects

Pat Levitt

Publications and source records attributed to Pat Levitt.

At least 37 records · Page 2Linked to original sources
PubMed2005

Applications of gene targeting technology to mental retardation and developmental disability research.

The human and mouse genome projects elucidated the sequence and position map of innumerous genes expressed in the central nervous system (CNS), advancing our ability to manipulate these sequences and create models to investigate regulation of gene expression and function. In this article, we reviewed gene targeting methodologies with emphasis on applications to CNS development and neurodevelopmental disorders.

Alleles↗
PubMed2005

Altered expression of 14-3-3 genes in the prefrontal cortex of subjects with schizophrenia.

Seven distinct 14-3-3 proteins are expressed in mammals. One of the 14-3-3 genes (eta) has been previously associated with decreased expression in the prefrontal cortex (PFC) of subjects with schizophrenia. DNA microarray analysis of the PFC of 10 subjects with schizophrenia and 10 matched controls indicated that the majority of 14-3-3 genes exhibited moderate to marked decreases in expression in schizophrenia, which were significant at the group level across all 10 comparisons (p<0.021). Selected changes in gene expression were further examined using in situ hybridization (ISH) in the same subject pairs as well as in four monkeys treated chronically with haloperidol and matched control animals. All analyses were performed blind to subject identity and diagnosis, or treatment. ISH analysis and multivariate analysis of covariance confirmed the significant decreases in expression of two 14-3-3 genes: beta -31.9%, zeta -18.2%. Two other 14-3-3 genes exhibited more modest decreases in expression levels that were significant only in pairwise comparisons that did not factor in post-mortem interval or tissue storage time: gamma -11.9%, eta -15.4%. In the PFC of haloperidol-treated monkeys, there was no difference in 14-3-3 zeta expression, while 14-3-3 beta increased 28% (p<0.05) as a result of neuroleptic treatment. Our results suggest that decreased expression of selected 14-3-3 genes is a common feature of schizophrenia and that the 14-3-3 beta transcript may be unique among the 14-3-3 genes in its increase in response to haloperidol and decrease in the disease state.

14-3-3 Proteins↗
PubMed2005

Disruption of interneuron development.

Disruption of gamma-aminobutyric acid (GABAergic) interneuron development during the embryonic and early postnatal periods can have profound neurological and behavioral consequences. Hepatocyte growth factor/scatter factor (HGF/SF) has been identified as an important molecular cue that may guide the movement of interneurons from their birthplace in the ganglionic eminences (GE) to their final resting place in the neocortex. In vitro studies demonstrate that decreased HGF/SF bioactivity in pallial and subpallial tissues is associated with a reduction in the number of cells migrating out of GE explants. The uPAR knockout mouse provides a unique opportunity to study the effects of interneuron disruption in vivo. uPAR-/- mice have reduced HGF/SF bioactivity in the GE during the period of interneuron development and a concomitant 50% reduction in the number of GABAergic interneurons seeding frontal and parietal regions of the cerebral cortex. Behaviorally, these mice display an increased susceptibility to seizures, heightened anxiety, and diminished social interaction. This article discusses the commonalities between the functional defects seen in uPAR-/- mice and those of humans with developmental disorders, such as epilepsy, schizophrenia, and autism. It is suggested that disruption of GABAergic interneuron development may represent a common point of convergence underlying the etiologies of many of these developmental disorders.

Animals↗
PubMed2004

Heat shock protein 12A shows reduced expression in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Deoxyribonucleic acid microarray analyses of dorsolateral prefrontal cortex (DLPFC) area 9 from 10 matched pairs of schizophrenic and control subjects revealed a consistent and significant decrease (p = .001; mean log2 signal difference = -.58) in transcript expression for a gene clone KIAA0417. This database entry has been recently annotated as two highly homologous members of a heat-shock protein family (HSPA12A and HSPA12B). METHODS: We followed up our initial results by in situ hybridization in subjects with schizophrenia, major depression, and a chronic haloperidol-treated nonhuman primate model. Furthermore, we investigated the distribution of HSPA12A and HSPA12B transcripts across the human and nonhuman primate brain. RESULTS: We found that HSPA12A (but not HSPA12B) is highly expressed in the human brain and shows a neuron- and region-specific transcript distribution, with strongest expression in the frontal and occipital cortical regions. HSPA12A messenger ribonucleic acid was significantly reduced (p < .01; mean log2 optical density difference = -.84) across subjects with schizophrenia but not in the DLPFC of subjects with major depression or in monkeys chronically treated with haloperidol. CONCLUSIONS: The data are consistent with metabolic alterations in schizophrenia, reflected in selective changes in the expression of certain genes encoding proteins involved in cellular metabolism or metabolic responsiveness.

Adult↗
PubMed2004

Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues.

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare specific clusters of autistic symptomatology to features of chromosome 15q11-q13 disorders. Paternally or maternally derived deficiencies of 15q11-q13 result in Prader-Willi or Angelman syndromes, and we first use a global approach to review potential autism susceptibility genes in the 15q11-q13 region. We then use a more trait-based approach to suggest possible ties between specific phenotypic characteristics of autism and Prader-Willi syndrome, namely savant-like skills. We conclude with insights from pathophysiological studies that implicate altered development of specific neuron types and circuits in the cerebral cortex as part of the pathophysiological processes associated with autism and mental retardation.

Animals↗
PubMed2004

Multiple roles of ephrins during the formation of thalamocortical projections: maps and more.

The functional architecture of the cerebral cortex is based on intrinsic connections that precisely link neurons from distinct cortical laminae as well as layer-specific afferent and efferent projections. Experimental strategies using in vitro assays originally developed by Friedrich Bonhoeffer have suggested that positional cues confined to individual layers regulate the assembly of local cortical circuits and the formation of thalamocortical projections. One of these wiring molecules is ephrinA5, a ligand for Eph receptor tyrosine kinases. EphrinA5 and Eph receptors exhibit highly dynamic expression patterns in distinct regions of the cortex and thalamus during early and late stages of thalamocortical and cortical circuit formation. In vitro assays suggest that ephrinA5 is a multifunctional wiring molecule for different populations of cortical and thalamic axons. Additionally, the expression patterns of ephrinA5 during cortical development are consistent with this molecule regulating, in alternative ways, specific components of thalamic and cortical connectivity. To test this directly, the organization of thalamocortical projections was examined in mice lacking ephrinA5 gene expression. The anatomical studies in ephrinA5 knockout animals revealed a miswiring of limbic thalamic projections and changes in neocortical circuits that were predicted from the expression pattern and the in vitro analysis of ephrinA5 function.

Animals↗
PubMed2004

Drug exposure early in life: functional repercussions of changing neuropharmacology during sensitive periods of brain development.

Exposure to drugs early in life can have long-lasting implications for brain structure and function. Effects on the developing nervous system, before homeostatic regulatory mechanisms are properly calibrated, differ from those on mature systems. Recent studies show that permanent alterations in brain pharmacology and cell signaling are induced by early drug exposure, producing hypo- or hyperresponsiveness to environmental or pharmacological challenges later in life. As a result, children exposed to drugs pre- or postnatally might respond abnormally to therapeutics used to treat the very disorders that they later exhibit as a result of their previous drug exposure.

Animals↗
PubMed2004

Sex-specific, postpuberty changes in mouse brain structures revealed by three-dimensional magnetic resonance microscopy.

Sexual dimorphism of brain structures has been reported in some species. We report that sex-dependent developmental structure changes exist in the C57Bl/6(J) mouse, a common model for the genetic analysis of brain function. High resolution, three-dimensional (3D) magnetic resonance microscopy (MRM) images were obtained in intact brains of male and female adult and peripubertal mice. The lateral and third ventricles, hippocampus, amygdala, striatum, and total brain were reconstructed in 3D. As observed in humans, there was overall cerebral growth from peripuberty to adulthood in both sexes. After correcting for the increased brain size, the hippocampus and amygdala were disproportionately larger in adult compared to peripubertal mice. Several sexual dimorphisms were also observed. The lateral ventricles were larger, while the amygdala (the left side in particular) was smaller in females compared to males. Lateral and third ventricles were reduced over time in males only, exhibiting a sex-specific developmental profile. The striatal size was uniform among the groups studied. The surface area of the segmented structures was assayed. Possible shape distortions were detected for the lateral ventricles, hippocampus, and overall brain structure based on a lack of covariance between the surface area and volumetric measurements. Although many sexually dimorphic changes are reported perinatally, our results suggest that there are additional sex-specific transformations that occur around puberty and persist in adulthood.

Animals↗
PubMed2004

Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders.

Neurodevelopmental disorders typically have complex endophenotypes, which can include abnormalities in neuronal excitability, processing of complex information, as well as behaviors such as anxiety and social interactions. Converging experimental and clinical evidence suggests that altered interneuron development may underlie part of the pathophysiological process of such disorders. Consistent with this, mice with abnormal hepatocyte growth factor signaling exhibit disturbances in the development of specific interneuron subclasses that are paralleled by seizure activity and a complex behavioral phenotype. Mutations in molecules that regulate different aspects of interneuron development could provide the heterogeneity in genetic susceptibility that, when combined with environmental disturbances, results in a phenotypic spectrum that serves as the hallmark pathophysiology for autism, mental retardation, schizophrenia and other neurodevelopmental disorders.

Animals↗
PubMed2004

Characterization of the genomic structure of the mouse limbic system-associated membrane protein (Lsamp) gene.

The Lsamp gene encodes the limbic system-associated membrane protein (LAMP) an immunoglobulin (Ig) superfamily member with three Ig domains and a glycosylphosphatidylinositol anchor. LAMP is expressed by neurons composing the limbic system, is highly conserved between rodents and human, and has structural and functional properties that substantiate its role in the formation of limbic circuits. We report here the genomic organization of the Lsamp gene. The Lsamp gene is composed of 11 exons distributed over 2.2 megabases (Mb). Two exons 1 are separated by approximately 1.6 Mb and contribute to the unusual large size of the gene. Alternative spliced Lsamp mRNAs are generated from distinct promoter regions associated with the two exons 1 that encode distinct signal peptides and thus generate identical native mature polypetides. Additional diversity is created by the use of two small exons to include an insertion of 23 amino acids within the polypeptide C-terminal region of the mature protein. The genomic features of the Lsamp gene described here indicate an intricate mechanism of gene expression regulation that may be relevant in the context of human neuropsychiatric and neurological disorders, where LAMP expression may be altered.

Alternative Splicing↗
PubMed2003

Regionally restricted expression of the transcription factor c-myc intron 1 binding protein during brain development.

Transcription factors regulate proliferation, differentiation, and regionalization of the central nervous system. In a screen of developing cerebral cortex, we identified the transcription factor c-myc intron 1 binding protein (mibp1) due to its abundant expression. In this study, we analyzed the temporal and spatial expression patterns of mibp1 mRNA in developing mouse brain to address the putative role of this transcription factor in neural differentiation. Northern hybridization studies revealed that mibp1 is expressed first in the mouse dorsal telencephalon at embryonic day (E) 14.5, during peak neuronal production. In situ hybridization experiments revealed that mibp1 expression in the cerebral wall is most abundant in postmitotic cells of the cortical plate and absent from proliferative zones. Moreover, mibp1 is restricted to dorsal telencephalon during embryogenesis with expression only in the cerebral wall, olfactory bulb, and hippocampus. N-myc, a potential target of mibp1 regulation, exhibited complementary, nonoverlapping expression patterns in the telencephalon with greatest expression in proliferating cells of the ventricular zone from E12.5 to E14.5; N-myc was absent from the telencephalon by E15.5. The specificity and timing of mibp1 expression in the cerebral cortex suggests a role in maintaining a state of neuronal differentiation in the dorsal telencephalon.

Animals↗
PubMed2003

Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction.

The generation of properly functioning circuits during brain development requires precise timing of cell migration and differentiation. Disruptions in the developmental plan may lead to neurological and psychiatric disorders. Neocortical circuits rely on inhibitory GABAergic interneurons, the majority of which migrate from subcortical sources. We have shown that the pleiotropic molecule hepatocyte growth factor/scatter factor (HGF/SF) mediates interneuron migration. Mice with a targeted mutation of the gene encoding urokinase plasminogen activator receptor (uPAR), a key component in HGF/SF activation and function, have decreased levels of HGF/SF and a 50% reduction in neocortical GABAergic interneurons at embryonic and perinatal ages. Disruption of interneuron development leads to early lethality in most models. Thus, the long-term consequences of such perturbations are unknown. Mice of the uPAR-/- strain survive until adulthood, and behavior testing demonstrates that they have an increased anxiety state. The uPAR-/- strain also exhibits spontaneous seizure activity and higher susceptibility to pharmacologically induced convulsions. The neocortex of the adult uPAR-/- mouse exhibits a dramatic region- and subtype-specific decrease in GABA-immunoreactive interneurons. Anterior cingulate and parietal cortical areas contain 50% fewer GABAergic interneurons compared with wild-type littermates. However, interneuron numbers in piriform and visual cortical areas do not differ from those of normal mice. Characterization of interneuron subpopulations reveals a near complete loss of the parvalbumin subtype, with other subclasses remaining intact. These data demonstrate that a single gene mutation can selectively alter the development of cortical interneurons in a region- and cell subtype-specific manner, with deficits leading to long-lasting changes in circuit organization and behavior.

Animals↗
PubMed2003

Distinct domains of the limbic system-associated membrane protein (LAMP) mediate discrete effects on neurite outgrowth.

The limbic system-associated membrane protein (LAMP) is a glycosylphosphatidylinositol-anchored glycoprotein with three immunoglobulin (Ig) domains that can either enhance or inhibit neurite outgrowth depending upon the neuronal population examined. In the present study, we investigate the domains responsible for these activities. Domain deletion revealed that the N-terminal IgI domain is necessary and sufficient for the neurite-promoting activity observed in hippocampal neurons. In contrast, inhibition of neurite outgrowth in SCG neurons, which is mediated by heterophilic interactions, requires full-length LAMP, although selective inhibition of the second Ig domain, but not the first or third domains, prevented the inhibitory effect. This indicates that the IgII domain of LAMP harbors the neurite-inhibiting activity, but only in the context of the full-length configuration. Covasphere-binding analyses demonstrate IgI/IgI interactions, but no interaction between IgII and any other domain, consistent with the biological activities that each domain mediates. The data suggest that LAMP may serve as a bifunctional guidance molecule, with distinct structural domains contributing to the promotion and inhibition of neurite outgrowth.

Animals↗
PubMed2003

Structural and functional maturation of the developing primate brain.

Descriptive studies have established that the developmental events responsible for the assembly of neural systems and circuitry are conserved across mammalian species. However, primates are unique regarding the time during which histogenesis occurs and the extended postnatal period during which myelination of pathways and circuitry formation occur and are then subsequently modified, particularly in the cerebral cortex. As in lower mammals, the framework for subcortical-cortical connectivity in primates is established before midgestation and already begins to remodel before birth. Association systems, responsible for modulating intracortical circuits that integrate information across functional domains, also form before birth, but their growth and reorganization extend into puberty. There are substantial differences across species in the patterns of development of specific neurochemical systems. The complexity is even greater when considering that the development of any particular cellular component may differ among cortical areas in the same primate species. Developmental and behavioral neurobiologists, psychologists, and pediatricians are challenged with understanding how functional maturation relates to the evolving anatomical organization of the human brain during childhood, and moreover, how genetic and environmental perturbations affect the adaptive changes exhibited by neural circuits in response to developmental disruption.

Animals↗
PubMed2002

Miswiring of limbic thalamocortical projections in the absence of ephrin-A5.

Axon guidance cues of the ephrin ligand family have been hypothesized to regulate the formation of thalamocortical connections, but in vivo evidence for such a role has not been examined directly. To test whether ephrin-mediated repulsive cues participate in sorting the projections originating from distinct thalamic nuclei, we analyzed the organization of somatosensory and anterior cingulate afferents postnatally in mice lacking ephrin-A5 gene expression. Projections from ventrobasal and laterodorsal nuclei to their respective sensory and limbic cortical areas developed normally. However, a portion of limbic thalamic neurons from the laterodorsal nucleus also formed additional projections to somatosensory cortical territories, thus maintaining inappropriate dual projections to multiple cortical regions. These results suggest that ephrin-A5 is not required for the formation of normal cortical projections from the appropriate thalamic nuclei, but rather acts as a guidance cue that restricts limbic thalamic axons from inappropriate neocortical regions.

Animals↗
PubMed2002

Complementary expression and heterophilic interactions between IgLON family members neurotrimin and LAMP.

Neurotrimin (Ntm) and the limbic system-associated membrane protein (LAMP) are members of the IgLON (LAMP, OBCAM, Ntm) family of glycorylphosphatidylinositol anchored neural cell adhesion molecules. We previously reported that LAMP and Ntm promote adhesion and neurite outgrowth via a homophilic mechanism, suggesting that these proteins promote the formation of specific neuronal circuits by homophilic interactions. In this report, we have further characterized the expression and binding specificity of Ntm. Using a newly generated monoclonal antibody to Ntm, we demonstrated that this protein is largely expressed in a complementary pattern to that of LAMP in the nervous system, with co-expression at a few sites. Ntm is expressed at high levels in sensory-motor cortex and, of particular note, is transiently expressed in neurons of cortical barrel fields and corresponding thalamic "barreloids." Binding of a recombinant, soluble form of Ntm to CHO cells expressing either Ntm or LAMP demonstrates that Ntm and LAMP interact both homophilically and heterophilically. In contrast to conventional growth-promoting activity of Ig superfamily members, LAMP strongly inhibits the outgrowth of Ntm-expressing dorsal root ganglion (DRG) neurons in a heterophilic manner. These anatomical and functional data support the concept that homophilic and heterophilic interactions between IgLON family members are likely to play a role in the specification of neuronal projections via growth promoting and inhibiting effects, respectively.

Animals↗