Rett syndrome is an X‐linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this... more
Rett syndrome is an X‐linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5–6 months old) symptomatic Mecp2‐heterozygous female mice with N‐acetyl cysteine conjugated to dendrimer (D‐NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2‐heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D‐NAC (10 mg/kg NAC) once weekly is more effic...
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Hypothermic circulatory arrest is a protective technique used when complete cessation of circulation is required during cardiac surgery. Prior efforts to decrease neurologic injury with the NMDA receptor antagonist MK801 were limited by... more
Hypothermic circulatory arrest is a protective technique used when complete cessation of circulation is required during cardiac surgery. Prior efforts to decrease neurologic injury with the NMDA receptor antagonist MK801 were limited by unacceptable side effects. We hypothesized that ketamine would provide neuroprotection without dose-limiting side effects. Canines were peripherally cannulated for cardiopulmonary bypass, cooled to 18°C, and underwent 90 minutes of circulatory arrest. Ketamine-treated canines (n=5; total dose 2.85 mg/kg) were compared to untreated controls (n=10). A validated neurobehavioral deficit score was obtained at 24, 48, and 72 hours (0=no deficits/normal exam; higher score represents increasing deficits). Biomarkers of neuronal injury in the cerebrospinal fluid were examined at baseline and at 8, 24, 48, and 72 hours. Brain histopathologic injury was scored at 72 hours (higher score indicates more necrosis and apoptosis). Ketamine-treated canines had significantly improved, lower neurobehavioral deficit scores compared to controls (overall p=0.003; 24 hours: median 72 vs. 112, p=0.030; 48 hours: 47 vs. 90, p=0.021; 72 hours: 30 vs. 89, p=0.069). Although the histopathologic injury scores of ketamine-treated canines (median 12) were lower than controls (16), there was no statistical difference (p=0.10). Levels of phosphorylated neurofilament-H and neuron specific enolase, markers of neuronal injury, were significantly lower in ketamine-treated animals (p=0.010 and =0.039, respectively). Ketamine significantly reduced neurologic deficits and biomarkers of injury in canines after hypothermic circulatory arrest. Ketamine represents a safe and approved medication that may be useful as a pharmacologic neuroprotectant during cardiac surgery with circulatory arrest.
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BACKGROUND Hypothermic circulatory arrest (HCA) is associated with neurologic morbidity, in part mediated by activation of the N-methyl-D-aspartate glutamate receptor causing excitotoxicity and neuronal apoptosis. Using a canine model, we... more
BACKGROUND Hypothermic circulatory arrest (HCA) is associated with neurologic morbidity, in part mediated by activation of the N-methyl-D-aspartate glutamate receptor causing excitotoxicity and neuronal apoptosis. Using a canine model, we hypothesized that the N-methyl-D-aspartate receptor antagonist MK801 would provide neuroprotection and that MK801 conjugation to dendrimer nanoparticles would improve efficacy. MATERIALS AND METHODS Male hound dogs were placed on cardiopulmonary bypass, cooled to 18°C, and underwent 90 min of HCA. Dendrimer conjugates (d-MK801) were prepared by covalently linking dendrimer surface OH groups to MK801. Six experimental groups received either saline (control), medium- (0.15 mg/kg) or high-dose (1.56 mg/kg) MK801, or low- (0.05 mg/kg), medium-, or high-dose d-MK801. At 24, 48, and 72 h after HCA, animals were scored by a standardized neurobehavioral paradigm (higher scores indicate increasing deficits). Cerebrospinal fluid was obtained at baseline, eight, 24, 48, and 72 h after HCA. At 72 h, brains were examined for histopathologic injury in a blinded manner (higher scores indicate more injury). RESULTS Neurobehavioral deficit scores were reduced by low-dose d-MK801 on postoperative day two (P < 0.05) and by medium-dose d-MK801 on postoperative day 3 (P = 0.05) compared with saline controls, but free drug had no effect. In contrast, high-dose free MK801 significantly improved histopathology scores compared with saline (P < 0.05) and altered biomarkers of injury in cerebrospinal fluid, with a significant reduction in phosphorylated neurofilament-H for high-dose MK801 versus saline (P < 0.05). CONCLUSIONS Treatment with MK-801 demonstrated significant improvement in neurobehavioral and histopathology scores after HCA, although not consistently across doses and conjugates.
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Research Interests: Electron Microscopy, Enzyme Inhibitors, Apoptosis, Medicine, Dogs, and 15 moreLearning and Memory, Glutamate, Brain, Complication, Animals, Male, Animal Model, Clinical Sciences, Apoptose, Entorhinal Cortex, Group, Cerebral protection, Cardiopulmonary bypass, Neuronal apoptosis, and Cardiovascular medicine and haematology
It has been proposed repeatedly that the noradrenergic (NE) system may exert an influence on cortical development. We have tested this proposition by examining synaptogenesis in the visual cortex of rats whose NE afferents were... more
It has been proposed repeatedly that the noradrenergic (NE) system may exert an influence on cortical development. We have tested this proposition by examining synaptogenesis in the visual cortex of rats whose NE afferents were selectively lesioned by injections of the neurotoxin 6-hydroxydopamine (6-OHDA). Control littermates were injected with equal volumes of vehicle. Montages of electron micrographs covering approximately 50 micrometers-wide strips of cortex were assembled from both groups of animals at 2,4,6,8,14, and 90 days of age. Synapse counts revealed a significantly higher density of synapses in the cortex of 6-OHDA-treated rats during the first week of postnatal life. The difference between the experimental and control rats was less apparent during the second postnatal week, and at day 90 the densities of synapses were similar for the two groups of animals. The enhanced density, which was the result of the increased number of Gray&#39;s type I synapses, was confined to the subplate region at day 2 but became more widespread in the cortex at subsequent stages of development. From these observations it would appear that the NE system exerts an inhibitory influence on synapse formation in the visual cortex in early postnatal life.
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The ontogeny of metabotropic excitatory amino acid receptors (mGluRs) in rat barrel field cortex was characterized by using receptor autoradiography and immunocytochemistry to test the hypothesis that changes in mGluR expression coincide... more
The ontogeny of metabotropic excitatory amino acid receptors (mGluRs) in rat barrel field cortex was characterized by using receptor autoradiography and immunocytochemistry to test the hypothesis that changes in mGluR expression coincide with the emergence of somatotopic patterns in this region. On postnatal days 1 (P1) and 3, [3H]glutamate binding to mGluRs was not distributed in a somatotopic pattern. By P5, mGluRs exhibited a whisker-related pattern, with higher densities of mGluRs in barrel centers than in surrounding cortex. Between P5 and P14 and at P60, the overall binding density remained higher in barrels than in surrounding cortex. At P60, a somatotopic pattern of binding was not apparent. The majority of mGluR sites in the barrel field were blocked by the metabotropic agonist trans-1-aminocyclopentane-1,3-dicarboxylic acid but were not significantly displaced by quisqualate. Immunocytochemical studies of phosphoinositide-linked mGluRs, mGluR5 and mGluR1alpha, showed that the developmental expression of mGluR5 mirrored that of the pattern of autoradiographically labeled mGluRs. The immature barrel field (ages P5-P14) was enriched in mGluR5, with greater concentrations of mGluR5 immunoreactivity in barrels than in surrounding cortex. Within barrel centers, mGluR5 was localized within the neuropil, on the surfaces of cell bodies and dendrites in layer IV. A somatotopic pattern of mGluR5 immunoreactivity persisted into adulthood, although the pattern was less pronounced after P14. In contrast, mGluR1alpha was never localized in a somatotopic pattern in barrel field cortex. We conclude from the developmental localization of mGluRs that the spatiotemporal regulated expression of these receptors may influence barrel maturation and plasticity.
Research Interests: Neuroscience, Aging, Biology, Immunohistochemistry, Medicine, and 15 moreAnimals, Medical Physiology, Long Term Depression, Rats, Barrel Cortex, Autoradiography, Receptor, Neuropil, Comparative Neurology, Neurosciences, Glutamic Acid, Neuroprotective Agents, Glutamate Receptor, Kainic acid, and NMDA receptor
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The Hawley H. Seiler Resident Award is presented annually to the resident with the oral presentation and manuscript deemed the best among those submitted for the competition. This Award was inaugurated in 1997 to honor Dr Seiler for his contributions and dedicated service to the Southern Thoracic...more
Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied... more
Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.
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BACKGROUND Hypothermic circulatory arrest (HCA) is associated with neurologic morbidity, in part mediated by activation of the N-methyl-D-aspartate glutamate receptor causing excitotoxicity and neuronal apoptosis. Using a canine model, we... more
BACKGROUND Hypothermic circulatory arrest (HCA) is associated with neurologic morbidity, in part mediated by activation of the N-methyl-D-aspartate glutamate receptor causing excitotoxicity and neuronal apoptosis. Using a canine model, we hypothesized that the N-methyl-D-aspartate receptor antagonist MK801 would provide neuroprotection and that MK801 conjugation to dendrimer nanoparticles would improve efficacy. MATERIALS AND METHODS Male hound dogs were placed on cardiopulmonary bypass, cooled to 18°C, and underwent 90 min of HCA. Dendrimer conjugates (d-MK801) were prepared by covalently linking dendrimer surface OH groups to MK801. Six experimental groups received either saline (control), medium- (0.15 mg/kg) or high-dose (1.56 mg/kg) MK801, or low- (0.05 mg/kg), medium-, or high-dose d-MK801. At 24, 48, and 72 h after HCA, animals were scored by a standardized neurobehavioral paradigm (higher scores indicate increasing deficits). Cerebrospinal fluid was obtained at baseline, eight, 24, 48, and 72 h after HCA. At 72 h, brains were examined for histopathologic injury in a blinded manner (higher scores indicate more injury). RESULTS Neurobehavioral deficit scores were reduced by low-dose d-MK801 on postoperative day two (P < 0.05) and by medium-dose d-MK801 on postoperative day 3 (P = 0.05) compared with saline controls, but free drug had no effect. In contrast, high-dose free MK801 significantly improved histopathology scores compared with saline (P < 0.05) and altered biomarkers of injury in cerebrospinal fluid, with a significant reduction in phosphorylated neurofilament-H for high-dose MK801 versus saline (P < 0.05). CONCLUSIONS Treatment with MK-801 demonstrated significant improvement in neurobehavioral and histopathology scores after HCA, although not consistently across doses and conjugates.
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Recent studies suggest that the cerebellum may have a significant role in repetitive behaviors. In primary complex motor stereotypies, typically developing children have repetitive movements usually involving rhythmic flapping/waving... more
Recent studies suggest that the cerebellum may have a significant role in repetitive behaviors. In primary complex motor stereotypies, typically developing children have repetitive movements usually involving rhythmic flapping/waving arm/hand movements. Similarly, the deer mouse animal model exhibits inherited repetitive behaviors, with increased frequencies of spontaneous jumping and rearing. In this study, data from both children with motor stereotypies and deer mice were used to investigate the role of the cerebellum in repetitive behaviors. The 3.0-T MRI volumetric imaging of the cerebellum was obtained in 20 children with primary complex motor stereotypies and 20 healthy controls. In deer mice, cerebellar volume (n = 7/group) and cell counts (n = 9/group) were compared between high- and low-activity animals. Levels of cerebellar neurotransmitters were also determined via HPLC (n = 10/group). In children with stereotypies, (a) there were a statistically significant reduction (compared to controls) in the white matter volume of the posterior cerebellar lobule VI-VII that negatively correlated with motor control and (b) an 8% increase in the anterior vermis gray matter that positively correlated with motor Stereotypy Severity Scores (SSS). In deer mice, (a) there was a significant increase in the volume of the anterior vermal granular cell layer that was associated with higher activity and (b) dentate nucleus cell counts were higher in high activity animals. Similar increases in volume were observed in anterior vermis in children with stereotypies and a deer mouse model of repetitive behaviors. These preliminary findings support the need for further investigation of the cerebellum in repetitive behaviors.
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From a neurobiologic perspective, Rett syndrome appears to disrupt the growth of axonodendritic connections among neurons. The cell packing density within the grey matter is increased but the total number of neurons is relatively normal,... more
From a neurobiologic perspective, Rett syndrome appears to disrupt the growth of axonodendritic connections among neurons. The cell packing density within the grey matter is increased but the total number of neurons is relatively normal, except for selected neuronal populations such as the nucleus basalis of Meynert (NBM) and the substantia nigra. Neurochemical assays of postmortem brain from patients with Rett syndrome patients demonstrate reductions in choline acetyltransferase (ChAT), the acetylcholine synthetic enzyme localized in NBM nerve terminals. In an animal model, early postnatal injury to the cholinergic pathways projected from the NBM causes permanent disruption of developing cholinergic neurons and a behavioral disorder on maze testing. The results suggest a mechanism by which early deficits in cholinergic and dopamine neurons projecting to the cerebral cortex from the brainstem and basal forebrain could disrupt axonodendritic development in the cerebral cortex. Studies in our laboratory are examining the mechanisms for these effects as well as the distribution and densities of neurotransmitter receptors in postmortem brains from Rett patients.
Research Interests: Neuroscience, Medicine, Dopamine, Brain, Humans, and 15 moreCerebral Cortex, Female, Animals, Acetylcholine, Basal forebrain, Synaptic Transmission, Rett syndrome, Neuropediatrics, Cholinergic Systems, Neural pathways, Nucleus Basalis, Neurosciences, Choline Acetyltransferase, Cell count, and Paediatrics and reproductive medicine
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BACKGROUND Hypothermic circulatory arrest (HCA) is a technique used for complex repair of the aorta, but it can be associated with neurologic morbidity. To better understand the molecular changes that underlie ischemic brain injury, we... more
BACKGROUND Hypothermic circulatory arrest (HCA) is a technique used for complex repair of the aorta, but it can be associated with neurologic morbidity. To better understand the molecular changes that underlie ischemic brain injury, we assessed gene expression and cytokine/chemokine polypeptide concentration in brain tissue and cerebrospinal fluid (CSF) of canines that underwent two hours of HCA. MATERIALS AND METHODS Adult male canines were cannulated peripherally for cardiopulmonary bypass, cooled to 18°C, and arrested for two hours. Animals were euthanized two, eight, or 24 hours post-HCA (n = 8 per group), and their brains were compared to brains from eight normal canines, using gene expression microarray analysis, cytokine assay, and histopathology. RESULTS Two to eight hours after HCA, pro-inflammatory cytokine mRNAs increased markedly, and gene expression was enriched within signaling pathways related to neuroinflammation or ischemic injury. Concentrations of pro-inflammatory cytokine polypeptides IL-6, IL-8, IL-1β, and CCL2 were very low in normal canine brain, whereas anti-inflammatory IL-10 and TGF-β1 were expressed at moderate levels. Pro-inflammatory cytokine concentrations rose robustly in cerebral tissue and CSF after HCA. IL-6 and IL-8 peaked at eight hours and declined at 24 hours, while IL-1β and CCL2 remained elevated. Concentrations of anti-inflammatory IL-10 and TGF-β1 were maintained after HCA, with a significant increase in TGF-β1 at 24 hours. CONCLUSIONS These cytokines represent potential diagnostic markers for ischemic neurologic injury that could be used to assess neurologic injury in patients undergoing HCA. The cellular mechanisms underlying this pro-inflammatory, ischemic-induced injury represent potential targets for neuroprotection in the future.
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Abstract Autism spectrum disorder (ASD) is a complex, multifaceted, developmental brain disorder that is based on behavioral criteria and is increasing in frequency. Despite decades of research, reliable biomarkers and effective... more
Abstract Autism spectrum disorder (ASD) is a complex, multifaceted, developmental brain disorder that is based on behavioral criteria and is increasing in frequency. Despite decades of research, reliable biomarkers and effective therapeutic approaches remain elusive. Here we provide a focused review of research literature that suggests an involvement of the neurotransmitter serotonin (5-HT) in the etiology of the disorder. We describe the role that 5-HT plays in the maturation of brain structure and function as relevant to the neuropathologies of ASD. We discuss the role of 5-HT in autoimmune disorders, inflammation, and the gut–brain axis, all of which have been associated with ASD and are identified as risk factors for maternal transmission. Our review supports the hypothesis that the interplay of peripheral and central 5-HT levels in the mother and offspring, and placental 5-HT synthesis impacts early brain development in genetically vulnerable individuals and result in the neuropathologies associated with ASD.
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Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2)... more
Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, deficits in synaptic- and circuit-homeostatic mechanisms, seizures, and sleep. In particular, we compare the overlapping and contrasting features between RTT and CDD in clinic and in preclinical studies. Finally, we discuss lessons learned from recent clinical trials while reviewing the findings from pre-clinical studies.
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After publication of the article [1], it has been brought to our attention that an author's name has been formatted incorrectly.
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Rett syndrome (RTT) is a neurodevelopmental disorder predominately affecting young females, caused by deficiency of the global transcriptional protein methyl CpG binding protein 2 (MeCP2). Osteoblasts express MeCP2 and girls with RTT... more
Rett syndrome (RTT) is a neurodevelopmental disorder predominately affecting young females, caused by deficiency of the global transcriptional protein methyl CpG binding protein 2 (MeCP2). Osteoblasts express MeCP2 and girls with RTT experience early onset osteoporosis, decreased bone mass and an increased fracture risk. There is no defined treatment for osteoporosis associated with RTT. The present study evaluated the effects of zoledronic acid (ZA), a third generation nitrogen-containing bisphosphonate with primarily anti-osteoclastic activity, in a mouse model of MeCP2 deficiency. Mice received weekly injections of 20μg/kg ZA for six weeks. Due to the shortened lifespan of hemizygous male (Mecp2-null) mice, treatment began at 3weeks of age for this group and corresponding wildtype (WT) male mice. Treatment for heterozygous (HET) and WT female mice began at 8weeks of age. Micro-computed tomography (micro-CT) and dynamic analyses of bone turnover were performed. ZA treatment led to...
Research Interests: Engineering, Endocrinology, Medicine, Biological Sciences, Osteoporosis, and 15 moreInternal Medicine, Cancellous bone, Mice, Bone, Animals, Male, Apposition, Rett syndrome, Cortical Bone, Bone remodeling, Imidazoles, X Ray Microtomography, Knockout Mice, Zoledronic acid, and Medical and Health Sciences
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Physiochemical characterization of dendrimer-N-acetylcysteine (D-NAC) conjugates. A) D-NAC chemical structure and proton NMR spectrum of D-NAC conjugate in DMSO. B) HPLC chromatogram of D-NAC with elution time at 19.65 min and free NAC... more
Physiochemical characterization of dendrimer-N-acetylcysteine (D-NAC) conjugates. A) D-NAC chemical structure and proton NMR spectrum of D-NAC conjugate in DMSO. B) HPLC chromatogram of D-NAC with elution time at 19.65 min and free NAC eluting at 6.14 min. C) Size and zeta potential measurements of G4-OH, bifunctional dendrimer and D-NAC conjugates. (TIFF 2366 kb)
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In September of 2011, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the International Rett Syndrome Foundation (IRSF) and... more
In September of 2011, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the International Rett Syndrome Foundation (IRSF) and the Rett Syndrome Research Trust (RSRT) convened a workshop involving a broad cross-section of basic scientists, clinicians and representatives from the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), the pharmaceutical industry and private foundations to assess the state of the art in animal studies of Rett syndrome (RTT). The aim of the workshop was to identify crucial knowledge gaps and to suggest scientific priorities and best practices for the use of animal models in preclinical evaluation of potential new RTT therapeutics. This review summarizes outcomes from the workshop and extensive follow-up discussions among participants, and includes: (1) a comprehensive summary of the physiological and behavioral phenotyp...
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Research Interests: Cardiology, Apoptosis, Caspases, Dogs, Models, and 15 moreCerebellum, Animals, Male, Anesthesia, Brain injury, Behavioral Animal Models, Clinical Sciences, Dentate Gyrus, Calpain, Basal ganglia, Breakdown, Biological markers, Immunoblotting, Brain injuries, and Cardiovascular medicine and haematology
D-NAC treatment did not prevent weight loss in Mecp2-null mice. Regression plots for body weights of WT (open squares-dotted line) and Mecp2-null mice treated with PBS (solid black circles-black line), NAC (red open circles-red line) and... more
D-NAC treatment did not prevent weight loss in Mecp2-null mice. Regression plots for body weights of WT (open squares-dotted line) and Mecp2-null mice treated with PBS (solid black circles-black line), NAC (red open circles-red line) and D-NAC (solid blue circles-blue line). With age, weight increased in all groups of mice. However the trajectory for all groups of Mecp2-null mice was less than in WT mice. (TIFF 236Â kb)
MTT cytotoxicity assay. No toxicity of G4-OH dendrimer, NAC, or dendrimer-conjugated NAC was observed in Mecp2-null primary mixed glial culture at 100 and 10 μg/ml concentrations. There was some toxicity with free NAC at 200 μg/ml (
Evaluation of NAC release from D-NAC was conducted in human pooled plasma. (A) To simulate an extracellular environment, 10 μM of GSH was added to the plasma containing D-NAC (3 mg/mL). D-NAC was stable in plasma for more than 48 h... more
Evaluation of NAC release from D-NAC was conducted in human pooled plasma. (A) To simulate an extracellular environment, 10 μM of GSH was added to the plasma containing D-NAC (3 mg/mL). D-NAC was stable in plasma for more than 48 h releasing ~ 5% of its payload. (B) For intracellular stimulation, 250 μM of GSH was used. D-NAC demonstrated faster NAC release (~ 80% of its payload) within 5 h suggesting that GSH cleaved the disulfide bonds. (JPEG 43 kb)
Neurobehavioral Scoring Scheme. Table of neurobehavioral subscores and their scoring scheme used to determine phenotypic severity in Mecp2-null mice. (PDF 40Â kb)
Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the adult brain and can prevent the severe loss of cortical 5-HT axons caused by the neurotoxin p-chloroamphetamine (PCA). However, it has not... more
Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the adult brain and can prevent the severe loss of cortical 5-HT axons caused by the neurotoxin p-chloroamphetamine (PCA). However, it has not been determined whether BDNF promotes the survival of 5-HT axons during PCA-insult or facilitates their regenerative sprouting after injury. We show here that BDNF fails to protect most 5-HT axons from PCA-induced degeneration. Instead, chronic BDNF infusions markedly stimulate the sprouting of both intact and PCA-lesioned 5-HT axons, leading to a hyperinnervation at the neocortical infusion site. BDNF treatment promoted the regrowth of 5-HT axons when initiated up to a month after PCA administration. The sprouted axons persisted in cortex for at least 5 weeks after terminating exogenous BDNF delivery. BDNF also encouraged the regrowth of the 5-HT plexus in the
Research Interests: Neuroscience, Serotonin, Humans, Cerebral Cortex, Animals, and 15 moreMale, The, Rat Brain, Neurotoxins, Nerve Regeneration, Rats, Time Factors, Degeneration, Recombinant Proteins, Cell Survival, Axons, Gene Expression Regulation, Functional Laterality, Psychology and Cognitive Sciences, and Medical and Health Sciences
Serotonergic (5-HT) axons from the raphe nuclei are among the earliest afferents to innervate the developing forebrain. The present study examined whether GAP-43, a growth-associated protein expressed on growing 5-HT axons, is necessary... more
Serotonergic (5-HT) axons from the raphe nuclei are among the earliest afferents to innervate the developing forebrain. The present study examined whether GAP-43, a growth-associated protein expressed on growing 5-HT axons, is necessary for normal 5-HT axonal outgrowth and terminal arborization during the perinatal period. We found a nearly complete failure of 5-HT immunoreactive axons to innervate the cortex and hippocam-pus in GAP-43–null (GAP43/) mice. Abnormal ingrowth of 5-HT axons was apparent on postnatal day 0 (P0); quantitative analysis of P7 brains revealed significant reductions in the density of 5-HT axons in the cortex and hippocampus of GAP43/mice relative to wild-type (WT) controls. In contrast, 5-HT axon density was normal in the striatum, septum, and amygdala and dramatically higher than normal in the thalamus of GAP43/ mice. Concentrations of serotonin and its me-
Research Interests: Neuroscience, Aging, Biology, Medicine, Brain development, and 15 moreHippocampus, Cerebral Cortex, Mice, Animals, Membrane transport proteins, Norepinephrine, Quantitative Analysis, Dorsal raphe, Axons, Knock Out Mice, Axon Outgrowth, Brain stem, Cell count, Psychology and Cognitive Sciences, and Medical and Health Sciences
Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation
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We tested the claim that the dopaminergic dysfunction of Rett Syndrome (RTT) also occurs in Mecp2-deficient mice that serve as a model of the syndrome. We used positron emission tomography (PET) to image dopamine D receptors (DR) and... more
We tested the claim that the dopaminergic dysfunction of Rett Syndrome (RTT) also occurs in Mecp2-deficient mice that serve as a model of the syndrome. We used positron emission tomography (PET) to image dopamine D receptors (DR) and transporters (DAT) in women with RTT and in Mecp2-deficient mice, and DR and DR density was measured in postmortem human tissue by autoradiography. Results showed 1) significantly reduced DR density in the striatum of women with RTT compared to control subjects. 2) PET imaging of mouse striatum similarly demonstrated significant reductions in DR density of 7-10 week-old hemizygous (Mecp2-null) and heterozygous (HET) mice compared to wild type (WT) mice. With age, the density of DR declined in WT mice but not HET mice. 3) In contrast, postmortem autoradiography revealed no group differences in the density of DR and DR in the caudate and putamen of RTT versus normal control subjects. 4) In humans and in the mouse model, PET revealed only marginal group di...
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Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the... more
Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome. To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporte...
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Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM)... more
Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically-relevant canine model of HCA-induced brain injury. Generation 6 (G6, ~6.7nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ~4.3nm), which were undetectable in the brain by 48h after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ~20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. ...
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Neurocognitive dysfunction and injury remain problematic after cardiac procedures requiring hypothermic circulatory arrest (HCA). Due to poor blood-brain barrier penetrance and toxicities associated with systemic drug therapies, clinical... more
Neurocognitive dysfunction and injury remain problematic after cardiac procedures requiring hypothermic circulatory arrest (HCA). Due to poor blood-brain barrier penetrance and toxicities associated with systemic drug therapies, clinical success has been elusive. Accordingly, we explored targeted dendrimer (a nanoparticle) drug therapies in our well-established canine model of HCA to characterize the biodistribution and cellular localization of these nanoparticles in areas of known neuronal apoptosis and necrosis. Class A, 27- to 30-kg male hounds were administered an initial intravenous bolus (10% of the total dose [200 mg]) of generation-six polyamidoamine dendrimer (6.7 nm) labeled with cyanine 5, and cardiopulmonary bypass with peripheral cannulation was initiated. After 90 minutes of HCA, 70% of the total dose was infused over a 6-hour period. The final 20% of the total dose was given 24 hours post-HCA. The brain was harvested 48 hours later (72 hours post-HCA) and analyzed for...
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Rett syndrome (RTT) is a neurodevelopmental disorder that results from mutations in the X-linked gene for methyl-CpG-binding protein 2 (MECP2). The underlying cellular mechanism for the sensory deficits in patients with RTT is largely... more
Rett syndrome (RTT) is a neurodevelopmental disorder that results from mutations in the X-linked gene for methyl-CpG-binding protein 2 (MECP2). The underlying cellular mechanism for the sensory deficits in patients with RTT is largely unknown. This study used the Bird mouse model of RTT to investigate sensory thalamocortical synaptic transmission in the barrel cortex of Mecp2-null mice. Electrophysiological results showed an excitation/inhibition (E/I) imbalance, biased towards inhibition, due to an increase in efficacy of postsynaptic GABAA receptors density rather than alterations in inhibitory network and presynaptic release properties. Enhanced inhibition impaired the transmission of tonic sensory signals from the thalamus to the somatosensory cortex. Previous morphological studies showed an upregulation of NMDA receptors in the neocortex of both RTT patients and Mecp2-null mice at early ages (Blue et al. 1999b; 2011). Although, AMPA and NMDA receptor-mediated excitatory synapti...
Research Interests:
Rett syndrome is an extremely disabling X-linked nervous system disorder that mainly affects girls in early childhood and causes autism-like behavior, severe intellectual disability, seizures, sleep disturbances, autonomic instability,... more
Rett syndrome is an extremely disabling X-linked nervous system disorder that mainly affects girls in early childhood and causes autism-like behavior, severe intellectual disability, seizures, sleep disturbances, autonomic instability, and other disorders due to mutations in the MeCP2 (methyl CpG-binding protein 2) transcription factor. The disorder targets synapses and synaptic plasticity and has been shown to disrupt the balance between glutamate excitatory synapses and GABAergic inhibitory synapses. In fact, it can be argued that Rett syndrome is primarily a disorder of synaptic plasticity and that agents that can correct this imbalance may have beneficial effects on brain development. This review briefly summarizes the link between disrupted synaptic plasticity mechanisms and Rett syndrome and early clinical trials that aim to target these abnormalities to improve the outcome for these severely disabled children.