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1.
Cereb Cortex ; 26(5): 1938-1956, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-25662825

RESUMEN

Frontal cortical dysfunction is thought to contribute to cognitive and behavioral features of autism spectrum disorders; however, underlying mechanisms are poorly understood. The present study sought to define how loss of Mecp2, the gene mutated in Rett syndrome (RTT), disrupts function in the murine medial prefrontal cortex (mPFC) using acute brain slices and behavioral testing. Compared with wildtype, pyramidal neurons in the Mecp2 null mPFC exhibit significant reductions in excitatory postsynaptic currents, the duration of excitatory UP-states, evoked population activity, and the ratio of NMDA:AMPA currents, as well as an increase in the relative fraction of NR2B currents. These functional changes are associated with reductions in the density of excitatory dendritic spines, the ratio of vesicular glutamate to GABA transporters and GluN1 expression. In contrast to recent reports on circuit defects in other brain regions, we observed no effect of Mecp2 loss on inhibitory synaptic currents or expression of the inhibitory marker parvalbumin. Consistent with mPFC hypofunction, Mecp2 nulls exhibit respiratory dysregulation in response to behavioral arousal. Our data highlight functional hypoconnectivity in the mPFC as a potential substrate for behavioral disruption in RTT and other disorders associated with reduced expression of Mecp2 in frontal cortical regions.


Asunto(s)
Potenciales de la Membrana , Proteína 2 de Unión a Metil-CpG/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Síndrome de Rett/genética , Potenciales de Acción , Animales , Señalización del Calcio , Espinas Dendríticas , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores , Potenciales Postsinápticos Inhibidores , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Respiración/genética , Síndrome de Rett/fisiopatología , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismo
2.
Curr Opin Ophthalmol ; 26(6): 458-63, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26367094

RESUMEN

PURPOSE OF REVIEW: Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of an acute optic neuropathy over the age 50 with an annual incidence of 2-10/100 000. Most patients are left with a permanent decrease in visual acuity and visual field loss. No approved treatment has conclusively reversed the process or prevented a second event that typically involves the previously unaffected eye. Many medical and surgical treatments have been proposed with conflicting results. The goal of this review is to present current data in order to permit clinicians and patients to make an educated decision about treatment. RECENT FINDINGS: Recently, there has been a flurry of case reports, small clinical trials and testing in animal models of NAION for various treatments for NAION and this review attempts to present the data concisely with the authors' opinions about the reliability of the data. SUMMARY: To date, there is no class I evidence of benefit for the treatment of NAION; however, the aphorism attributed to Carl Sagan, PhD aptly applies: 'Absence of evidence is not evidence of absence'.


Asunto(s)
Neuropatía Óptica Isquémica , Corticoesteroides , Animales , Humanos , Incidencia , Neuropatía Óptica Isquémica/terapia , Factores de Riesgo , Agudeza Visual
3.
JAMA ; 311(16): 1641-51, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24756514

RESUMEN

IMPORTANCE: Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use. OBJECTIVE: To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between -2 dB and -7 dB. The mean age was 29 years and all but 4 participants were women. INTERVENTIONS: Low-sodium weight-reduction diet plus the maximally tolerated dosage of acetazolamide (up to 4 g/d) or matching placebo for 6 months. MAIN OUTCOMES AND MEASURES: The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to -32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6. RESULTS: The mean improvement in PMD was greater with acetazolamide (1.43 dB, from -3.53 dB at baseline to -2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from -3.53 dB to -2.82 dB; n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P = .050). Mean improvements in papilledema grade (acetazolamide: -1.31, from 2.76 to 1.45; placebo: -0.61, from 2.76 to 2.15; treatment effect, -0.70; 95% CI, -0.99 to -0.41; P < .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47; P = .003) and its 10-item neuro-ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: -7.50 kg, from 107.72 kg to 100.22 kg; placebo: -3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, -4.05 kg, 95% CI, -6.27 to -1.83 kg; P < .001). CONCLUSIONS AND RELEVANCE: In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function. The clinical importance of this improvement remains to be determined. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01003639.


Asunto(s)
Acetazolamida/uso terapéutico , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Dieta Hiposódica , Seudotumor Cerebral/tratamiento farmacológico , Trastornos de la Visión/tratamiento farmacológico , Adulto , Terapia Combinada , Femenino , Humanos , Masculino , Seudotumor Cerebral/complicaciones , Seudotumor Cerebral/dietoterapia , Calidad de Vida , Resultado del Tratamiento , Trastornos de la Visión/etiología , Pérdida de Peso
4.
J Neurosci ; 32(40): 13860-72, 2012 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-23035095

RESUMEN

Excitatory-inhibitory imbalance has been identified within specific brain microcircuits in models of Rett syndrome (RTT) and other autism spectrum disorders (ASDs). However, macrocircuit dysfunction across the RTT brain as a whole has not been defined. To approach this issue, we mapped expression of the activity-dependent, immediate-early gene product Fos in the brains of wild-type (Wt) and methyl-CpG-binding protein 2 (Mecp2)-null (Null) mice, a model of RTT, before and after the appearance of overt symptoms (3 and 6 weeks of age, respectively). At 6 weeks, Null mice exhibit significantly less Fos labeling than Wt in limbic cortices and subcortical structures, including key nodes in the default mode network. In contrast, Null mice exhibit significantly more Fos labeling than Wt in the hindbrain, most notably in cardiorespiratory regions of the nucleus tractus solitarius (nTS). Using nTS as a model, whole-cell recordings demonstrated that increased Fos expression in Nulls at 6 weeks of age is associated with synaptic hyperexcitability, including increased frequency of spontaneous and miniature EPSCs and increased amplitude of evoked EPSCs in Nulls. No such effect of genotype on Fos or synaptic function was seen at 3 weeks. In the mutant forebrain, reduced Fos expression, as well as abnormal sensorimotor function, were reversed by the NMDA receptor antagonist ketamine. In light of recent findings that the default mode network is hypoactive in autism, our data raise the possibility that hypofunction within this meta-circuit is a shared feature of RTT and other ASDs and is reversible.


Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Proteína 2 de Unión a Metil-CpG/fisiología , Red Nerviosa/fisiopatología , Prosencéfalo/fisiopatología , Núcleo Solitario/fisiopatología , Animales , Cerebelo/metabolismo , Cerebelo/fisiopatología , Modelos Animales de Enfermedad , Femenino , Regulación del Desarrollo de la Expresión Génica , Genes fos , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG/deficiencia , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Noqueados , Potenciales Postsinápticos Miniatura/efectos de los fármacos , Potenciales Postsinápticos Miniatura/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Especificidad de Órganos , Técnicas de Placa-Clamp , Prosencéfalo/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Síndrome de Rett/genética , Síndrome de Rett/fisiopatología , Filtrado Sensorial/efectos de los fármacos , Filtrado Sensorial/fisiología , Núcleo Solitario/química , Núcleo Solitario/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología
5.
J Neurosci ; 32(5): 1803-10, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22302819

RESUMEN

Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.


Asunto(s)
Benzamidas/metabolismo , Modelos Animales de Enfermedad , Agonismo Parcial de Drogas , Receptor trkB/agonistas , Receptor trkB/metabolismo , Mecánica Respiratoria/efectos de los fármacos , Síndrome de Rett/metabolismo , Animales , Femenino , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fosforilación/efectos de los fármacos , Fosforilación/genética , Mecánica Respiratoria/genética , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/genética
6.
J Neurosci ; 31(34): 12318-29, 2011 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-21865474

RESUMEN

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are highly expressed in the nucleus tractus solitarius (nTS), the principal target of cardiovascular primary afferent input to the brainstem. However, little is known about the role of BDNF signaling in nTS in cardiovascular homeostasis. We examined whether BDNF in nTS modulates cardiovascular function in vivo and regulates synaptic and/or neuronal activity in isolated brainstem slices. Microinjection of BDNF into the rat medial nTS (mnTS), a region critical for baroreflex control of sympathetic outflow, produced dose-dependent increases in mean arterial pressure (MAP), heart rate (HR), and lumbar sympathetic nerve activity (LSNA) that were blocked by the tyrosine kinase inhibitor K252a. In contrast, immunoneutralization of endogenous BDNF (anti-BDNF), or microinjection of K252a alone, decreased MAP, HR, and LSNA. The effects of anti-BDNF were abolished by blockade of ionotropic glutamate receptors, indicating a role for glutamate signaling in the response to BDNF. In vitro, BDNF reduced the amplitude of miniature EPSCs as well as solitary tract (TS) evoked EPSC amplitude and action potential discharge (APD) in second-order nTS neurons. BDNF effects on EPSCs were independent of GABAergic signaling and abolished by AMPA receptor blockade. In contrast, K252a increased spontaneous EPSC frequency and TS evoked EPSC amplitude. BDNF also attenuated APD evoked by injection of depolarizing current into second-order neurons, indicating reduced intrinsic neuronal excitability. Our data demonstrate that BDNF signaling in mnTS plays a tonic role in regulating cardiovascular function, likely via modulation of primary afferent glutamatergic excitatory transmission and neural activity.


Asunto(s)
Vías Autónomas/fisiología , Factor Neurotrófico Derivado del Encéfalo/fisiología , Fenómenos Fisiológicos Cardiovasculares , Neuronas/fisiología , Núcleo Solitario/fisiología , Transmisión Sináptica/fisiología , Potenciales de Acción/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/antagonistas & inhibidores , Masculino , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-Dawley
7.
Ophthalmol Retina ; 6(4): 318-324, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34742898

RESUMEN

PURPOSE: To determine how frequently patients who present to an emergency department (ED) with a retinal artery occlusion (RAO) undergo brain imaging and cardiovascular testing and are hospitalized. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Patients who presented to an ED with an RAO in the National Emergency Department Sample (NEDS), a nationally representative United States database. METHODS: The NEDS was queried to identify patients who presented to an ED with the primary diagnosis of RAO between 2006 and 2014. Patient and hospital characteristics were evaluated, and a multivariable regression was performed to determine predictors of hospitalization. Testing was categorized into 3 groups: (1) brain imaging performed using computed tomography or magnetic resonance; (2) carotid imaging performed using ultrasound, computed tomography, or magnetic resonance; and (3) cardiac testing performed using electrocardiogram or echocardiogram. The number of tests performed for each category was recorded. MAIN OUTCOME MEASURES: Proportions of patients undergoing brain imaging, carotid imaging, or cardiac testing. Rate and predictors of hospitalization. RESULTS: Among 259 343 582 ED visits, 2802 had a primary diagnosis of RAO. Patients were mostly aged ≥65 years (59%) and male (54%). Hypertension (59%), dyslipidemia (36%), and diabetes (20%) were the most common preexisting cardiovascular diseases. Brain imaging, carotid imaging, and cardiac testing were performed in 20.3%, 7.1%, and 23.8% of the patients, respectively; at least 1 test from each of these 3 categories was performed in 4.1% of the patients. Half of the patients were hospitalized. Factors that increased the chances of hospitalization included the following (P < 0.05): age of <45 years; female sex; a history of smoking; presenting to a metropolitan hospital and having giant cell arteritis, carotid artery disease, atrial fibrillation, cardiac valve disease, obesity, dyslipidemia, hypertension, diabetes, and chronic ischemic heart disease. CONCLUSIONS: Most patients who presented to an ED with an RAO did not receive emergency brain imaging, carotid imaging, or basic cardiac testing. A multidisciplinary approach is needed to raise awareness that RAOs should be treated as a precursor of stroke or a stroke equivalent.


Asunto(s)
Hipertensión , Oclusión de la Arteria Retiniana , Accidente Cerebrovascular , Estudios Transversales , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Oclusión de la Arteria Retiniana/diagnóstico , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos
8.
J Neurosci ; 30(15): 5303-10, 2010 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-20392952

RESUMEN

Postnatal deficits in brain-derived neurotrophic factor (BDNF) are thought to contribute to pathogenesis of Rett syndrome (RTT), a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2-null mice, a model of RTT, BDNF deficits are most pronounced in structures important for autonomic and respiratory control, functions that are severely affected in RTT patients. However, relatively little is known about how these deficits affect neuronal function or how they may be linked to specific RTT endophenotypes. To approach these issues, we analyzed synaptic function in the brainstem nucleus tractus solitarius (nTS), the principal site for integration of primary visceral afferent inputs to central autonomic pathways and a region in which we found markedly reduced levels of BDNF in Mecp2 mutants. Our results demonstrate that the amplitude of spontaneous miniature and evoked EPSCs in nTS neurons is significantly increased in Mecp2-null mice and, accordingly, that mutant cells are more likely than wild- type cells to fire action potentials in response to primary afferent stimulation. These changes occur without any increase in intrinsic neuronal excitability and are unaffected by blockade of inhibitory GABA currents. However, this synaptopathy is associated with decreased BDNF availability in the primary afferent pathway and can be rescued by application of exogenous BDNF. On the basis of these findings, we hypothesize that altered sensory gating in nTS contributes to cardiorespiratory instability in RTT and that nTS is a site at which restoration of normal BDNF signaling could help reestablish normal homeostatic controls.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína 2 de Unión a Metil-CpG/metabolismo , Neuronas/fisiología , Núcleo Solitario/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Potenciales de Acción/fisiología , Animales , Modelos Animales de Enfermedad , Potenciales Evocados/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Técnicas In Vitro , Bulbo Raquídeo/fisiología , Proteína 2 de Unión a Metil-CpG/deficiencia , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Noqueados , Inhibición Neural/fisiología , Neuronas Aferentes/fisiología , Síndrome de Rett , Vías Visuales/fisiología , Ácido gamma-Aminobutírico/metabolismo
9.
J Neurosci ; 29(39): 12187-95, 2009 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-19793977

RESUMEN

Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the Methyl-CpG-binding protein-2 (MECP2) gene and is characterized by derangements in cognition, behavior, motor control, respiration and autonomic homeostasis, as well as seizures. Deficits in norepinephrine (NE) are thought to contribute to RTT pathogenesis, but little is known about how MeCP2 regulates function of noradrenergic neurons. We therefore characterized morphological, electrical, and neurochemical properties of neurons in the locus ceruleus (LC), the major source of noradrenergic innervation to the central neuraxis, in Mecp2 mutant mice. We found that MeCP2 null LC neurons are electrically hyperexcitable, smaller in size, and express less of the NE-synthesizing enzyme tyrosine hydroxylase (TH) compared with wild-type neurons. Increased excitability of mutant neurons is associated with reductions in passive membrane conductance and the amplitude of the slow afterhyperpolarization. Studies in Mecp2 heterozygotes, which are mosaic for the null allele, demonstrated that electrical hyperexcitability and reduced neuronal size are cell-autonomous consequences of MeCP2 loss, whereas reduced TH expression appears to reflect both cell-autonomous and non-autonomous influences. Finally, we found reduced levels of TH and norepinephrine in cingulate cortex, a forebrain target of the LC. Thus, genetic loss of MeCP2 results in a somewhat paradoxical LC neuron phenotype, characterized by both electrical hyperexcitability and reduced indices of noradrenergic function. Given the importance of the LC in modulating activity in brainstem and forebrain networks, we hypothesize that dysregulation of LC function in the absence of MeCP2 plays a key role in the pathophysiology of RTT.


Asunto(s)
Modelos Animales de Enfermedad , Locus Coeruleus/fisiopatología , Síndrome de Rett/fisiopatología , Animales , Femenino , Masculino , Potenciales de la Membrana/genética , Proteína 2 de Unión a Metil-CpG/deficiencia , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Síndrome de Rett/genética
10.
Dis Model Mech ; 13(11)2020 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-33361117

RESUMEN

Reduced expression of brain-derived neurotrophic factor (BDNF) and impaired activation of the BDNF receptor, tropomyosin receptor kinase B (TrkB; also known as Ntrk2), are thought to contribute significantly to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous studies from this and other laboratories have shown that enhancing BDNF expression and/or TrkB activation in Mecp2-deficient mouse models of RTT can ameliorate or reverse abnormal neurological phenotypes that mimic human RTT symptoms. The present study reports on the preclinical efficacy of a novel, small-molecule, non-peptide TrkB partial agonist, PTX-BD4-3, in heterozygous female Mecp2 mutant mice, a well-established RTT model that recapitulates the genetic mosaicism of the human disease. PTX-BD4-3 exhibited specificity for TrkB in cell-based assays of neurotrophin receptor activation and neuronal cell survival and in in vitro receptor binding assays. PTX-BD4-3 also activated TrkB following systemic administration to wild-type and Mecp2 mutant mice and was rapidly cleared from the brain and plasma with a half-life of ∼2 h. Chronic intermittent treatment of Mecp2 mutants with a low dose of PTX-BD4-3 (5 mg/kg, intraperitoneally, once every 3 days for 8 weeks) reversed deficits in two core RTT symptom domains - respiration and motor control - and symptom rescue was maintained for at least 24 h after the last dose. Together, these data indicate that significant clinically relevant benefit can be achieved in a mouse model of RTT with a chronic intermittent, low-dose treatment paradigm targeting the neurotrophin receptor TrkB.


Asunto(s)
Actividad Motora , Receptor trkB/metabolismo , Síndrome de Rett/fisiopatología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Heterocigoto , Hipocampo/patología , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones Mutantes , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Síndrome de Rett/sangre , Síndrome de Rett/patología , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química
11.
Front Neurol ; 11: 358, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32581988

RESUMEN

Background: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that presents with higher-order visual dysfunction with relative sparing of memory and other cognitive domains, and it is most commonly associated with Alzheimer's disease pathology. There is a lack of data regarding the presentation of PCA to non-cognitive specialists. Therefore, we collected clinical data from neuro-ophthalmologists regarding the presentation of PCA to their practices and compared data to published cohorts and a published survey of cognitive specialists. Methods: Members of the North American Neuro-Ophthalmology Society Listserv (NANOSnet) were invited to complete an online, retrospective, chart-review data-entry survey regarding their patients with PCA, and REDCap was used for data collection. Results: Data for 38 patients were entered by 12 neuro-ophthalmologists. Patient mean age at presentation was 67.8 years, and 74% of patients were women. Difficulty reading was reported at presentation by 91% of patients, and poor performance on color vision, stereopsis, and visual field testing (performed reliably by 36/38 patients) were common findings. Most patients who were treated were treated with donepezil and/or memantine. Conclusions: Compared to published data from cognitive specialists, patients presenting to neuro-ophthalmology with PCA were more likely to be older and female and have a reading complaint. Reliable visual field testing was the norm with homonymous defects in the majority of patients. The neuro-ophthalmologist plays an important role in diagnosing PCA in older adults with unexplained visual signs and symptoms, and future studies of PCA should involve multiple specialists in order to advance our understanding of PCA and develop effective treatments.

12.
Eur J Neurosci ; 30(4): 602-10, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19674087

RESUMEN

Rett syndrome (RTT) is a progressive developmental disorder resulting from loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), a transcription regulatory protein. The RTT phenotype is complex and includes severe cardiorespiratory abnormalities, dysautonomia and behavioral symptoms of elevated stress. These findings have been attributed to an apparent hyperactivity of the sympathetic nervous system due to defects in brainstem development; however, the possibility that the peripheral sympathoadrenal axis itself is abnormal has not been explored. The present study demonstrates that the adrenal medulla and sympathetic ganglia of Mecp2 null mice exhibit markedly reduced catecholamine content compared with wild-type controls. Despite this, null animals exhibit significantly higher plasma epinephrine levels, suggesting enhanced secretory granule function in adrenal chromaffin cells. Indeed, we find that Mecp2 null chromaffin cells exhibit a cell autonomous hypersecretory phenotype characterized by significant increases in the speed and size of individual secretory granule fusion events in response to electrical stimulation. These findings appear to indicate accelerated formation and enhanced dilation of the secretory granule fusion pore, resulting in elevated catecholamine release. Our data therefore highlight abnormal catecholamine function in the sympathoadrenal axis as a potential source of autonomic dysfunction in RTT. These findings may help to explain the apparent 'overactivity' of the sympathetic nervous system reported in patients with RTT.


Asunto(s)
Glándulas Suprarrenales/fisiopatología , Gránulos Cromafines/metabolismo , Modelos Animales de Enfermedad , Síndrome de Rett/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Glándulas Suprarrenales/química , Glándulas Suprarrenales/patología , Animales , Cromatografía Líquida de Alta Presión , Dopamina/análisis , Electrofisiología , Epinefrina/análisis , Femenino , Inmunohistoquímica , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Ratones Noqueados , Mutación , Norepinefrina/análisis , Ganglio Cervical Superior/química , Sistema Nervioso Simpático/patología
13.
J Neurosci ; 27(40): 10912-7, 2007 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-17913925

RESUMEN

Rett syndrome (RTT) is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is thought to act as a transcriptional repressor of brain-derived neurotrophic factor (BDNF), Mecp2 null mice, which develop an RTT-like phenotype, exhibit progressive deficits in BDNF expression. These deficits are particularly significant in the brainstem and nodose cranial sensory ganglia (NGs), structures critical for cardiorespiratory homeostasis, and may be linked to the severe respiratory abnormalities characteristic of RTT. Therefore, the present study used Mecp2 null mice to further define the role of MeCP2 in regulation of BDNF expression and neural function, focusing on NG neurons and respiratory control. We find that mutant neurons express significantly lower levels of BDNF than wild-type cells in vitro, as in vivo, under both depolarizing and nondepolarizing conditions. However, BDNF levels in mutant NG cells can be increased by chronic depolarization in vitro or by treatment of Mecp2 null mice with CX546, an ampakine drug that facilitates activation of glutamatergic AMPA receptors. Ampakine-treated Mecp2 null mice also exhibit marked functional improvement, characterized by restoration of normal breathing frequency and minute volume. These data demonstrate that BDNF expression remains plastic in Mecp2 null mice and raise the possibility that ampakine compounds could be of therapeutic value in the treatment of RTT.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depsipéptidos/efectos de los fármacos , Dioxoles/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Piperidinas/uso terapéutico , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/fisiopatología , Análisis de Varianza , Anestésicos Locales/farmacología , Animales , Animales Recién Nacidos , Factor Neurotrófico Derivado del Encéfalo/genética , Células Cultivadas , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ganglio Nudoso/citología , Pletismografía/métodos , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Tetrodotoxina/farmacología
14.
Eur J Neurosci ; 28(3): 510-20, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18702723

RESUMEN

Brain-derived neurotrophic factor (BDNF) is required during the prenatal period for normal development of the respiratory central command; however, the underlying mechanisms remain unknown. To approach this issue, the present study examined BDNF regulation of fetal respiratory rhythm generation in the preBötzinger complex (preBötC) of the mouse, using transverse brainstem slices obtained from prenatal day 16.5 animals. BDNF application (100 ng/mL, 15 min) increased the frequency of rhythmic population activity in the preBötC by 43%. This effect was not observed when preparations were exposed to nerve growth factor (100 ng/mL, 30 min) or pretreated with the tyrosine kinase inhibitor K252a (1 h, 200 nm), suggesting that BDNF regulation of preBötC activity requires activation of its cognate tyrosine receptor kinase, TrkB. Consistent with this finding, single-cell reverse transcription-polymerase chain reaction experiments showed that one third of the rhythmically active preBötC neurons analysed expressed TrkB mRNA. Moreover, 20% expressed BDNF mRNA, suggesting that the preBötC is both a target and a source of BDNF. At the network level, BDNF augmented activity of preBötC glutamatergic neurons and potentiated glutamatergic synaptic drives in respiratory neurons by 34%. At the cellular level, BDNF increased the activity frequency of endogenously bursting neurons by 53.3% but had no effect on basal membrane properties of respiratory follower neurons, including the Ih current. Our data indicate that BDNF signalling through TrkB can acutely modulate fetal respiratory rhythm in association with increased glutamatergic drive and bursting activity in the preBötC.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/farmacología , Feto , Bulbo Raquídeo/anatomía & histología , Respiración/efectos de los fármacos , Centro Respiratorio/efectos de los fármacos , Centro Respiratorio/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Animales Recién Nacidos , Calcio/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Feto/anatomía & histología , Feto/efectos de los fármacos , Feto/fisiología , Edad Gestacional , Ácido Glutámico/metabolismo , Bulbo Raquídeo/efectos de los fármacos , Ratones , Neuronas/fisiología , Técnicas de Placa-Clamp , Periodicidad , Embarazo , Receptor trkB/genética , Receptor trkB/metabolismo , Centro Respiratorio/anatomía & histología , Transducción de Señal/fisiología , Sinapsis/metabolismo
15.
Respir Physiol Neurobiol ; 164(1-2): 55-63, 2008 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-18534925

RESUMEN

Severely arrhythmic breathing is a hallmark of Rett syndrome (RTT) and profoundly affects quality of life for patients and their families. The last decade has seen the identification of the disease-causing gene, methyl-CpG-binding protein 2 (Mecp2) and the development of mouse models that phenocopy many aspects of the human syndrome, including breathing dysfunction. Recent studies have begun to characterize the breathing phenotype of Mecp2 mutant mice and to define underlying electrophysiological and neurochemical deficits. The picture that is emerging is one of defects in synaptic transmission throughout the brainstem respiratory network associated with abnormal expression in several neurochemical signaling systems, including brain-derived neurotrophic factor (BDNF), biogenic amines and gamma-amino-butyric acid (GABA). Based on such findings, potential therapeutic strategies aimed at improving breathing by targeting deficits in neurochemical signaling are being explored. This review details our current understanding of respiratory dysfunction and underlying mechanisms in RTT with a particular focus on insights gained from mouse models.


Asunto(s)
Epigénesis Genética , Trastornos Respiratorios , Síndrome de Rett/complicaciones , Síndrome de Rett/genética , Animales , Dioxoles/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Mutación/genética , Piperidinas/uso terapéutico , Trastornos Respiratorios/tratamiento farmacológico , Trastornos Respiratorios/etiología , Trastornos Respiratorios/genética , Trastornos Respiratorios/patología , Centro Respiratorio/metabolismo , Centro Respiratorio/fisiopatología , Sistema Respiratorio/metabolismo , Sistema Respiratorio/fisiopatología
16.
J Neurosci ; 26(42): 10911-5, 2006 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-17050729

RESUMEN

Disruptions in brain-derived neurotrophic factor (BDNF) expression are proposed to contribute to the molecular pathogenesis of Rett syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in methyl-CpG-binding protein-2 (MeCP2). Although MeCP2 is a transcriptional regulator of BDNF, it is unknown how MeCP2 mutations affect transsynaptic BDNF signaling. Our findings demonstrate an early, abnormal neurosecretory phenotype in MeCP2-deficient neurons characterized by significant increases in the percentage of cellular BDNF content available for release. However, loss of MeCP2 also results in deficits in total cell BDNF content that are developmentally regulated in a cell-type-specific manner. Thus, the net effect of MeCP2 loss on absolute BDNF secretion changes with age and is determined by both the amount of BDNF available for release and progressive declines in total cellular BDNF. We propose, therefore, that loss of MeCP2 function disrupts transsynaptic BDNF signaling by perturbing the normal balance between BDNF protein levels and secretion. However, mutant neurons are capable of secreting wild-type levels of BDNF in response to high-frequency electrical stimulation. In addition, we found elevated exocytic function in Mecp2(-/y) adrenal chromaffin cells, indicating that the Mecp2 null mutation is associated with alterations of neurosecretion that are not restricted to BDNF. These findings are the first examples of abnormal neuropeptide and catecholamine secretion in a mouse model of RTT.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Factor Neurotrófico Derivado del Encéfalo/genética , Regulación de la Expresión Génica/genética , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Sinapsis/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/fisiología , Células Cultivadas , Proteína 2 de Unión a Metil-CpG/deficiencia , Ratones , Ratones Noqueados , Transducción de Señal/genética , Sinapsis/genética
17.
eNeuro ; 4(6)2017.
Artículo en Inglés | MEDLINE | ID: mdl-29333487

RESUMEN

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al., 1999), a transcriptional regulatory protein (Klose et al., 2005). Mouse models of RTT (Mecp2 mutants) exhibit excitatory hypoconnectivity in the medial prefrontal cortex (mPFC; Sceniak et al., 2015), a region critical for functions that are abnormal in RTT patients, ranging from learning and memory to regulation of visceral homeostasis (Riga et al., 2014). The present study was designed to test the hypothesis that increasing the activity of mPFC pyramidal neurons in heterozygous female Mecp2 mutants (Hets) would ameliorate RTT-like symptoms, including deficits in respiratory control and long-term retrieval of auditory conditioned fear. Selective activation of mPFC pyramidal neurons in adult animals was achieved by bilateral infection with an AAV8 vector expressing excitatory hm3D(Gq) DREADD (Designer Receptors Exclusively Activated by Designer Drugs) (Armbruster et al., 2007) under the control of the CamKIIa promoter. DREADD activation in Mecp2 Hets completely restored long-term retrieval of auditory conditioned fear, eliminated respiratory apneas, and reduced respiratory frequency variability to wild-type (Wt) levels. Reversal of respiratory symptoms following mPFC activation was associated with normalization of Fos protein levels, a marker of neuronal activity, in a subset of brainstem respiratory neurons. Thus, despite reduced levels of MeCP2 and severe neurological deficits, mPFC circuits in Het mice are sufficiently intact to generate normal behavioral output when pyramidal cell activity is increased. These findings highlight the contribution of mPFC hypofunction to the pathophysiology of RTT and raise the possibility that selective activation of cortical regions such as the mPFC could provide therapeutic benefit to RTT patients.


Asunto(s)
Cognición/fisiología , Corteza Prefrontal/fisiopatología , Células Piramidales/fisiología , Respiración , Síndrome de Rett/fisiopatología , Animales , Percepción Auditiva/fisiología , Condicionamiento Psicológico/fisiología , Drogas de Diseño , Modelos Animales de Enfermedad , Miedo/fisiología , Femenino , Vectores Genéticos , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones de la Cepa 129 , Ratones Endogámicos BALB C , Ratones Transgénicos , Distribución Aleatoria , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo
18.
Trends Neurosci ; 39(2): 100-113, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26830113

RESUMEN

Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders.


Asunto(s)
Síndrome de Rett/genética , Síndrome de Rett/terapia , Investigación Biomédica Traslacional/tendencias , Animales , Ensayos Clínicos como Asunto/métodos , Epigénesis Genética/genética , Humanos , Mutación/genética , Síndrome de Rett/diagnóstico , Investigación Biomédica Traslacional/métodos
19.
J Neurosci ; 22(23): 10399-407, 2002 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-12451139

RESUMEN

Brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent modifications of neuronal connectivity and synaptic strength, including establishment of hippocampal long-term potentiation (LTP). To shed light on mechanisms underlying BDNF-dependent synaptic plasticity, the present study was undertaken to characterize release of native BDNF from newborn rat hippocampal neurons in response to physiologically relevant patterns of electrical field stimulation in culture, including tonic stimulation at 5 Hz, bursting stimulation at 25 and 100 Hz, and theta-burst stimulation (TBS). Release was measured using the ELISA in situ technique, developed in our laboratory to quantify secretion of native BDNF without the need to first overexpress the protein to nonphysiological levels. Each stimulation protocol resulted in a significant increase in BDNF release that was tetrodotoxin sensitive and occurred in the absence of glutamate receptor activation. However, 100 Hz tetanus and TBS, stimulus patterns that are most effective in inducing hippocampal LTP, were significantly more effective in releasing native BDNF than lower-frequency stimulation. For all stimulation protocols tested, removal of extracellular calcium, or blockade of N-type calcium channels, prevented BDNF release. Similarly, depletion of intracellular calcium stores with thapsigargin and treatment with dantrolene, an inhibitor of calcium release from caffeine-ryanodine-sensitive stores, markedly inhibited activity-dependent BDNF release. Our results indicate that BDNF release can encode temporal features of hippocampal neuronal activity. The dual requirement for calcium influx through N-type calcium channels and calcium mobilization from intracellular stores strongly implicates a role for calcium-induced calcium release in activity-dependent BDNF secretion.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Hipocampo/metabolismo , Neuronas/metabolismo , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/efectos de los fármacos , Células Cultivadas , Dantroleno/farmacología , Estimulación Eléctrica/métodos , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática/métodos , Hipocampo/citología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Neuronas/citología , Neuronas/efectos de los fármacos , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Rianodina/farmacología , Canales de Sodio/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Tetrodotoxina/farmacología , Factores de Tiempo
20.
J Neurosci ; 23(20): 7685-9, 2003 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-12930808

RESUMEN

Genetic loss of brain-derived neurotrophic factor (BDNF) severely disrupts brainstem control of respiratory rhythmogenesis in newborn mice; however, the sites at which BDNF acts to regulate respiratory rhythmogenesis are unknown. Using immunochemical and multiplex RT-PCR analysis in mouse brainstem slices, we report that the BDNF receptor, Tyrosine kinase B (TrkB), is strongly expressed in the pre-Bötzinger complex (PBC), the presumed site for rhythm generation, and colocalizes with neurokinin 1 (NK1), a marker of neurons critical for breathing. The period of the respiratory rhythm generated by PBC neurons in vitro was increased by 30% after BDNF treatment (100 ng/ml) and not by nerve growth factor (100 ng/ml) or BDNF (100 ng/ml) in the presence of the tyrosine kinase inhibitor K252a (200 nm). Both synaptic and voltage-dependent properties of PBC neurons were modified by BDNF. Synaptic currents underlying spontaneous rhythmic bursts and glutamate-evoked currents were enhanced by 66 and 33%, respectively. BDNF reduced the Ih current amplitude in rhythmic neurons by 46% and shifted its activation curve by -17 mV. All neurons expressing TrkB mRNA (n = 8) also expressed mRNAs for the Ih current [hyperpolarization-activated cyclic nucleotide-sensitive cation nonselective channel (HCN1)], and three of four NK1-positive neurons coexpressed TrkB and HCN mRNA. Six of 16 PBC neurons expressed BDNF mRNA, supporting the possibility of autocrine and paracrine actions of BDNF within the respiratory pattern generator. Our data demonstrate that BDNF can modulate respiratory network activity through TrkB signaling in rhythmic PBC neurons.


Asunto(s)
Neuronas/fisiología , Receptor trkB/metabolismo , Centro Respiratorio/metabolismo , Centro Respiratorio/fisiología , Animales , Animales Recién Nacidos , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/farmacología , Células Cultivadas , Conductividad Eléctrica , Potenciales Postsinápticos Excitadores , Inmunohistoquímica , Bulbo Raquídeo/anatomía & histología , Bulbo Raquídeo/fisiología , Ratones , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Periodicidad , ARN Mensajero/biosíntesis , Receptor trkB/análisis , Receptor trkB/genética , Centro Respiratorio/citología , Transcripción Genética
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