Early Defects of GABAergic Synapses in the Brain Stem of a MeCP2 Mouse Model of Rett Syndrome

2008 ◽  
Vol 99 (1) ◽  
pp. 112-121 ◽  
Author(s):  
L. Medrihan ◽  
E. Tantalaki ◽  
G. Aramuni ◽  
V. Sargsyan ◽  
I. Dudanova ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Brain Stem ◽  
Rett Syndrome ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Ventrolateral Medulla ◽  
Diagnostic Tools ◽  
The Brain

Rett syndrome is a neurodevelopmental disorder caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) and represents the leading genetic cause for mental retardation in girls. MeCP2-mutant mice have been generated to study the molecular mechanisms of the disease. It was suggested that an imbalance between excitatory and inhibitory neurotransmission is responsible for the behavioral abnormalities, although it remained largely unclear which synaptic components are affected and how cellular impairments relate to the time course of the disease. Here, we report that MeCP2 KO mice present an imbalance between inhibitory and excitatory synaptic transmission in the ventrolateral medulla already at postnatal day 7. Focusing on the inhibitory synaptic transmission we show that GABAergic, but not glycinergic, synaptic transmission is strongly depressed in MeCP2 KO mice. These alterations are presumably due to both decreased presynaptic γ-aminobutyric acid (GABA) release with reduced levels of the vesicular inhibitory transmitter transporter and reduced levels of postsynaptic GABAA-receptor subunits α2 and α4. Our data indicate that in the MeCP2 −/y mice specific synaptic molecules and signaling pathways are impaired in the brain stem during early postnatal development. These observations mandate the search for more refined diagnostic tools and may provide a rationale for the timing of future therapeutic interventions in Rett patients.

scholarly journals MicroRNA network changes in the brain stem underlie the development of hypertension

2015 ◽  
Vol 47 (9) ◽  
pp. 388-399 ◽  
Author(s):  
Danielle DeCicco ◽  
Haisun Zhu ◽  
Anthony Brureau ◽  
James S. Schwaber ◽  
Rajanikanth Vadigepalli
Keyword(s):  
Brain Stem ◽  
Differential Expression ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Network Motif ◽  
Microrna Expression ◽  
Negative Regulator ◽  
Ventrolateral Medulla ◽  
Wistar Kyoto ◽  
The Brain

Hypertension is a major chronic disease whose molecular mechanisms remain poorly understood. We compared neuroanatomical patterns of microRNAs in the brain stem of the spontaneous hypertensive rat (SHR) to the Wistar Kyoto rat (WKY, control). We quantified 419 well-annotated microRNAs in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), from SHR and WKY rats, during three main stages of hypertension development. Changes in microRNA expression were stage- and region-dependent, with a majority of SHR vs. WKY differential expression occurring at the hypertension onset stage in NTS versus at the prehypertension stage in RVLM. Our analysis identified 24 microRNAs showing time-dependent differential expression in SHR compared with WKY in at least one brain region. We predicted potential gene regulatory targets corresponding to catecholaminergic processes, neuroinflammation, and neuromodulation using the miRWALK and RNA22 databases, and we tested those bioinformatics predictions using high-throughput quantitative PCR to evaluate correlations of differential expression between the microRNAs and their predicted gene targets. We found a novel regulatory network motif consisting of microRNAs likely downregulating a negative regulator of prohypertensive processes such as angiotensin II signaling and leukotriene-based inflammation. Our results provide new evidence on the dynamics of microRNA expression in the development of hypertension and predictions of microRNA-mediated regulatory networks playing a region-dependent role in potentially altering brain-stem cardiovascular control circuit function leading to the development of hypertension.

scholarly journals Spreading Depression Can Be Elicited in Brain Stem of Immature But Not Adult Rats

2003 ◽  
Vol 90 (4) ◽  
pp. 2163-2170 ◽  
Author(s):  
Frank Richter ◽  
Sven Rupprecht ◽  
Alfred Lehmenkühler ◽  
Hans-Georg Schaible
Keyword(s):  
Brain Stem ◽  
Time Course ◽  
Spreading Depression ◽  
Chloride Ions ◽  
Extracellular Potassium ◽  
Peak Time ◽  
Adult Rats ◽  
Extracellular Potassium Concentration ◽  
Nmda Receptor Blocker ◽  
The Brain

Spreading depression (SD), a neuronal mechanism involved in brain pathophysiology, occurs in brain areas with high neuronal density such as the cerebral cortex. By contrast, the brain stem is thought to be resistant to SD. Here we show that DC shifts resembling cortical SD can be elicited in rat brain stem by topical application of KCl but not by pricking the brain stem. However, this was only possible until postnatal day 13, and, in addition, susceptibility for SD had to be enhanced. The latter was achieved by superfusion of the brain stem for 45 min with a solution containing acetate instead of chloride ions. Transient asphyxia or hypoxia by 2 min breathing 6% O2 in N2 had a similar effect. Negative brain stem DC deflections were paralleled by an increase of extracellular potassium concentration ≤40 mM and were spreading, but unlike cortical SD they were not inducible by glutamate and N-methyl-d-aspartate (NMDA). Time course and slope of brain stem SD either resembled cortical SD or were long-lasting and sustained. The latter stopped normal breathing. Different from cortical SD, negative brain stem DC deflections were changed in their slope (mostly converted into sustained shape, peak time was significantly prolonged, decline-time and duration were prolonged), but not abolished by the NMDA receptor blocker MK-801. Thus we demonstrate that the immature brain stem has the capacity to generate negative DC shifts, which could be relevant as a risk factor in newborn brain stem function.

Role of the brain stem in generating the 2- to 6-Hz oscillation in sympathetic nerve discharge

1993 ◽  
Vol 265 (5) ◽  
pp. R1026-R1035 ◽  
Author(s):  
S. Zhong ◽  
Z. S. Huang ◽  
G. L. Gebber ◽  
S. M. Barman
Keyword(s):  
Brain Stem ◽  
Sympathetic Nerve ◽  
Cervical Spinal Cord ◽  
Ventrolateral Medulla ◽  
Population Activity ◽  
A Value ◽  
Decerebrate Cats ◽  
The Brain ◽  
Nerve Discharge

We tested the hypothesis that brain stem circuits normally generate a 2- to 6-Hz oscillation in sympathetic nerve discharge (SND). Experiments were performed on baroreceptor-denervated decerebrate cats and urethan-anesthetized rats in which renal or splanchnic SND was recorded along with field potentials (population activity) from sites in the rostral ventrolateral medulla, medullary raphe, or medullary lateral tegmental field. Our major findings were as follows. 1) Population activity recorded from the three medullary regions contained a 2- to 6-Hz oscillation. 2) The 2- to 6-Hz oscillation in population activity recorded from some medullary sites was correlated to that in SND. Peak coherence in the 2- to 6-Hz band approached a value of 1 in some cases. 3) Whereas cervical spinal cord transection abolished or markedly reduced SND, the 2- to 6-Hz oscillation in medullary activity was essentially unchanged. These results support the view that the 2- to 6-Hz oscillation in SND can be generated in the brain stem of cats and rats.

Effects of insulin on the cardiovascular integrating mechanisms of brain stem in cats

1993 ◽  
Vol 265 (4) ◽  
pp. E609-E616 ◽  
Author(s):  
S. W. Kuo ◽  
J. H. Hsieh ◽  
W. C. Wu ◽  
H. T. Horng ◽  
L. R. Shian ◽  
...  
Keyword(s):  
Brain Stem ◽  
Cardiovascular Responses ◽  
Serum Glucose ◽  
Ventrolateral Medulla ◽  
Reticular Nucleus ◽  
Motor Nucleus ◽  
Renal Nerve ◽  
Pressor Responses ◽  
The Brain ◽  
Stimulation Of

In 65 cats anesthetized with alpha-chloralose and urethane, the effects of insulin on cardiovascular responses to stimulation of various structures in the brain stem were studied. The threshold dose of insulin injected intravenously that produced systemic hypoglycemia was 5-10 U/kg. Subthreshold hypoglycemic doses of insulin were used intracerebroventricularly (0.25 U/kg) or intracerebrally (2 mU in 200 nl). Sixty minutes after intravenous insulin, when serum glucose concentrations decreased from 158 to 43 mg/100 ml, pressor responses to stimulation of the periaqueductal gray of midbrain (PAG), locus coeruleus (LC), dorsal medulla (DM), ventrolateral medulla (VLM), and parvocellular reticular nucleus (PVC) decreased significantly. Depressor and bradycardiac response to stimulation of paramedian reticular nucleus or dorsal motor nucleus of vagus (DMV) decreased significantly as well. Thirty minutes after intracerebroventricular insulin, pressor responses of PAG, DM, and the bradycardiac response of DMV decreased significantly. Thirty minutes after intracerebral insulin, pressor responses and renal nerve activities of LC (but not PAG), VLM, DM, and PVC decreased significantly. A similar but faster onset (5 min) of depression of cardiovascular responses on stimulating the LC, VLM, DM, and PVC was observed in another six acutely midcollicular-decerebrate cats recovered from halothane anesthesia. These findings suggest that insulin directly inhibits the vasomotor structures of the brain stem and decreases the pressor responses to stimulation.

PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

2008 ◽  
Vol 294 (4) ◽  
pp. R1304-R1311 ◽  
Author(s):  
Melissa M. J. Farnham ◽  
Qun Li ◽  
Ann K. Goodchild ◽  
Paul M. Pilowsky
Keyword(s):  
Blood Pressure ◽  
Brain Stem ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Intrathecal Administration ◽  
Ventrolateral Medulla ◽  
Cell Group ◽  
Nerve Activity ◽  
The Brain

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide present in the rat brain stem. The extent of its localization within catecholaminergic groups and bulbospinal sympathoexcitatory neurons is not established. Using immunohistochemistry and in situ hybridization, we determined the extent of any colocalization with catecholaminergic and/or bulbospinal projections from the brain stem was determined. PACAP mRNA was found in tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the C1-C3 cell groups. In the rostral ventrolateral medulla (RVLM), PACAP mRNA was found in 84% of the TH-ir neurons and 82% of bulbospinal TH-ir neurons. The functional significance of these PACAP mRNA positive bulbospinal neurons was tested by intrathecal administration of PACAP-38 in anaesthetized rats. Splanchnic sympathetic nerve activity doubled (110%) and heart rate rose significantly (19%), although blood pressure was unaffected. In addition, as previously reported, PACAP was found in the A1 cell group but not in the A5 cell group or in the locus coeruleus. The RVLM is the primary site responsible for the tonic and reflex control of blood pressure through the activity of bulbospinal presympathetic neurons, the majority of which contain TH. The results indicate 1) that pontomedullary neurons containing both TH and PACAP that project to the intermediolateral cell column originate from C1-C3 and not A5, and 2) intrathecal PACAP-38 causes a prolonged, sympathoexcitatory effect.

Enhanced Hypoxia Susceptibility in Hippocampal Slices From a Mouse Model of Rett Syndrome

2009 ◽  
Vol 101 (2) ◽  
pp. 1016-1032 ◽  
Author(s):  
Marc Fischer ◽  
Julia Reuter ◽  
Florian J. Gerich ◽  
Belinda Hildebrandt ◽  
Sonja Hägele ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Neurodevelopmental Disorder ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Synaptic Function ◽  
Cell Swelling ◽  
Arterial Oxygen ◽  
Ca1 Pyramidal Neurons

Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-chromosomal MECP2 gene encoding for the transcriptional regulator methyl CpG binding protein 2 (MeCP2). Rett patients suffer from episodic respiratory irregularities and reduced arterial oxygen levels. To elucidate whether such intermittent hypoxic episodes induce adaptation/preconditioning of the hypoxia-vulnerable hippocampal network, we analyzed its responses to severe hypoxia in adult Rett mice. The occurrence of hypoxia-induced spreading depression (HSD)—an experimental model for ischemic stroke—was hastened in Mecp2− /y males. The extracellular K+ rise during HSD was attenuated in Mecp2− /y males and the input resistance of CA1 pyramidal neurons decreased less before HSD onset. CA1 pyramidal neurons were smaller and more densely packed, but the cell swelling during HSD was unaffected. The intrinsic optical signal and the propagation of HSD were similar among the different genotypes. Basal synaptic function was intact, but Mecp2− /y males showed reduced paired-pulse facilitation and higher field potential/fiber volley ratios, but no increased seizure susceptibility. Synaptic failure during hypoxia was complete in all genotypes and the final degree of posthypoxic synaptic recovery indistinguishable. Cellular ATP content was normal in Mecp2− /y males, but their hematocrit was increased as was HIF-1α expression throughout the brain. This is the first study showing that in Rett syndrome, the susceptibility of telencephalic neuronal networks to hypoxia is increased; the underlying molecular mechanisms apparently involve disturbed K+ channel function. Such an increase in hypoxia susceptibility may potentially contribute to the vulnerability of male Rett patients who are either not viable or severely disabled.

scholarly journals Transneuronal tracing of neural pathways that regulate hindlimb muscle blood flow

2007 ◽  
Vol 292 (4) ◽  
pp. R1532-R1541 ◽  
Author(s):  
T.-K. Lee ◽  
J. H. Lois ◽  
J. H. Troupe ◽  
T. D. Wilson ◽  
B. J. Yates
Keyword(s):  
Blood Flow ◽  
Brain Stem ◽  
Pseudorabies Virus ◽  
Muscle Blood Flow ◽  
Ventrolateral Medulla ◽  
Cell Group ◽  
Sympathetic Outflow ◽  
Survival Times ◽  
Left And Right ◽  
The Brain

Despite considerable interest in the neural mechanisms that regulate muscle blood flow, the descending pathways that control sympathetic outflow to skeletal muscles are not adequately understood. The present study mapped these pathways through the transneuronal transport of two recombinant strains of pseudorabies virus (PRV) injected into the gastrocnemius muscles in the left and right hindlimbs of rats: PRV-152 and PRV-BaBlu. To prevent PRV from being transmitted to the brain stem via motor circuitry, a spinal transection was performed just below the L2 level. Infected neurons were observed bilaterally in all of the areas of the brain that have previously been shown to contribute to regulating sympathetic outflow: the medullary raphe nuclei, rostral ventrolateral medulla (RVLM), rostral ventromedial medulla, A5 adrenergic cell group region, locus coeruleus, nucleus subcoeruleus, and the paraventricular nucleus of the hypothalamus. The RVLM, the brain stem region typically considered to play the largest role in regulating muscle blood flow, contained neurons infected following the shortest postinoculation survival times. Approximately half of the infected RVLM neurons were immunopositive for tyrosine hydroxylase, indicating that they were catecholaminergic. Many (47%) of the RVLM neurons were dually infected by the recombinants of PRV injected into the left and right hindlimb, suggesting that the central nervous system has a limited capacity to independently regulate blood flow to left and right hindlimb muscles.

scholarly journals Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mirko Luoni ◽  
Serena Giannelli ◽  
Marzia Tina Indrigo ◽  
Antonio Niro ◽  
Luca Massimino ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Protein Translation ◽  
Mutant Mice ◽  
Gene Encoding ◽  
Strong Immune Response ◽  
Intravenous Injections ◽  
Protein Levels ◽  
Mecp2 Protein ◽  
The Brain

Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.

scholarly journals MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021 ◽  
Vol 12 ◽  
Author(s):  
Katrina V. Good ◽  
John B. Vincent ◽  
Juan Ausió
Keyword(s):  
Rett Syndrome ◽  
Neuronal Development ◽  
Neurodevelopmental Disorder ◽  
Epigenetic Mark ◽  
Initial Development ◽  
Genetic Ablation ◽  
Developmental Regression ◽  
The Stability ◽  
The Brain

Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

Differential Time Course Activation of the Brain Stem Catecholaminergic Groups following Chronic Adrenalectomy

1992 ◽  
Vol 56 (2) ◽  
pp. 125-132 ◽  
Author(s):  
Joël Lachuer ◽  
Michel Buda ◽  
Marcel Tappaz
Keyword(s):  
Brain Stem ◽  
Time Course ◽  
The Brain
Sign in / Sign up

Export Citation Format

Share Document