Biogenic amines and their metabolites are differentially affected in the Mecp2-deficient mouse brain

International audienceBACKGROUND: Rett syndrome (RTT, MIM #312750) is a severe neurological disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Female patients are affected with an incidence of 1/15000 live births and develop normally from birth to 6-18 months of age before the onset of deficits in autonomic, cognitive, motor functions (stereotypic hand movements, impaired locomotion) and autistic features. Studies on Mecp2 mouse models, and specifically null mice, revealed morphological and functional alterations of neurons. Several functions that are regulated by bioaminergic nuclei or peripheral ganglia are impaired in the absence of Mecp2. RESULTS: Using high performance liquid chromatography, combined with electrochemical detection (HPLC/EC) we found that Mecp2(-/y) mice exhibit an alteration of DA metabolism in the ponto-bulbar region at 5 weeks followed by a more global alteration of monoamines when the disease progresses (8 weeks). Hypothalamic measurements suggest biphasic disturbances of norepinephrine and serotonin at pathology onset (5 weeks) that were found stabilized later on (8 weeks). Interestingly, the postnatal nigrostriatal dopaminergic deficit identified previously does not parallel the reduction of the other neurotransmitters investigated. Finally, dosage in cortical samples do not suggest modification in the monoaminergic content respectively at 5 and 8 weeks of age. CONCLUSIONS: We have identified that the level of catecholamines and serotonin is differentially affected in Mecp2(-/y) brain areas in a time-dependent fashion

Noradrénaline, maturation et fonctionnement du réseau respiratoire central (Etude in vivo et in vitro chez le foetus et le nouveau-né de souris normales ou mutantes)

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Monoamine oxidase A-deficiency and noradrenergic respiratory regulations in neonatal mice.

In vitro experiments were performed on brainstem-spinal cord preparations from mouse neonates to compare the noradrenergic regulations of the respiratory network in the control C3H/HeJ strain and the transgenic Tg8 strain which has been created from the C3H/HeJ strain by deletion of the gene encoding monoamine oxidase A (MAOA), the main enzyme for serotonin degradation. In both control and MAOA-deficient strains, we show: (i). that the pontine A5 area exerts a potent inhibitory modulation on the respiratory rhythm generator; (ii). that noradrenaline application induces a tonic phrenic activity; and (iii). that noradrenaline increases the respiratory rhythm. The latter effect is however delayed and weak in the Tg8 strain. Therefore, MAOA-deficiency has only slightly altered the noradrenergic regulations of the respiratory network

Mouse models of Kcnq2 dysfunction

International audienceVariants in the Kv7.2 channel subunit encoded by the KCNQ2 gene cause epileptic disorders ranging from a benign form with self-limited epileptic seizures and normal development to severe forms with intractable epileptic seizures and encephalopathy. The biological mechanisms involved in these neurological diseases are still unclear. The disease remains intractable in patients affected by the severe form. Over the past 20 years, KCNQ2 models have been developed to elucidate pathological mechanisms and to identify new therapeutic targets. The diversity of Kcnq2 mouse models has proven invaluable to access neuronal networks and evaluate the associated cognitive deficits. This review summarizes the available models and their contribution to our current understanding of KCNQ2 epileptic disorders

Complexe de pré-Bötzinger et automatisme respiratoire

À la naissance, le mammifère doit impérativement respirer afin d’oxygéner son sang. Puis, au cours de sa vie, il produira spontanément plusieurs centaines de millions de mouvements respiratoires, qu’il soit homme, souris ou éléphant. La commande nerveuse responsable de l’automatisme respiratoire est élaborée par un réseau complexe de neurones du tronc cérébral au sein duquel une région contenant des neurones respiratoires pacemaker (NRP) joue un rôle crucial : le complexe de pré-Bötzinger. Les mécanismes électrophysiologiques, moléculaires et génétiques impliqués dans le fonctionnement et la maturation du complexe de pré-Bötzinger sont discutés dans cette revue

Contribution des co-transporteurs cation chlorure KCC2 et NKCC1, à la maturation et la modulation des réseaux locomoteurs spinaux

Le cerveau et la moelle épinière adultes sont câblés pour traiter l information sensorielle et la transformer en patrons d activité cohérents qui forment la base de la perception du monde extérieur et de la motricité. Ces connexions très précises, loin d être complètement établies à la naissance, sont affinées par l activité électrique. Des activités spontanées (AS) peuvent être générées en l absence de stimulation extrinsèque au système considéré. Au niveau de la moelle épinière, les AS sont responsables des mouvements spontanés et des tremblements myocloniques observés chez tous les mammifères immatures y compris chez l humain. Elles constituent en quelque sorte les premiers pas du réseau locomoteur, ce qui signifie d une part, qu elles apparaissent avant l émergence d une activité de type locomotrice, et d autre part, qu elles participent à la mise en place et au raffinement d un réseau moteur fonctionnel. La locomotion est générée par des réseaux de neurones localisés au niveau de la moelle épinière lombaire. Ces neurones constituent le générateur de rythme locomoteur (ou CPG, pour central pattern generator ). Contrairement aux AS, l activité locomotrice est déclenchée par une stimulation du réseau. Le patron locomoteur de décharges rythmiques est alterné de chaque côté de la moelle spinale, et entre les racines lombaires qui innervent des muscles extenseurs et fléchisseurs.The mature brain and spinal cord are precisely wired to process sensory information into coherent patterns of activity that form the basis of our perception and motor behaviors. This precise wiring is not fully developed at birth. The pattern of connections that emerges during prenatal development only roughly approximates the final wiring. This initially coarse pattern of connections is subsequently refined by activity-dependent mechanisms that match precisely the presynaptic neurons to their appropriate target cells. In spinal cord, spontaneous activity (SA) is responsible for spontaneous limb movements and myoclonic twitching observed in all immature mammals, including human babies. SA can be seen as the first steps of the locomotor network since its participates in the development of the locomotor system.Locomotion is produced by neural networks located in the spinal cord (Central Pattern Generators (CPGs). Activation of CPGs, evokes a fictive locomotor pattern consisting of alternation between the motor bursts on the left and right sides of the spinal cord, as well as alternation between flexor and extensor bursts on the same side. Operation of neural networks depends on the balance between excitation and inhibition. At early stages of development, neuronal assemblies are hyperexcitable mainly because of GABA and glycine, the major inhibitory neurotransmitters in adults,that are depolarizing. GABA and glycine action depends on the intracellular concentration of chloride ([Cl-]i) which is finely regulated by specific cation-chloride co-transporters, called KCC2 and NKCC1.AIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

Muscarinic receptors and alpha2-adrenoceptors interact to modulate the respiratory rhythm in mouse neonates.

The respiratory rhythm generator (RRG) is modulated by several endogenous substances, including acetylcholine (ACh) and noradrenaline (NA) that interact in several modulatory processes. To know whether ACh and NA interacted to modulate the RRG activity, we used medullary "en bloc" and slice preparations from neonatal mice where the RRG has been shown to receive a facilitatory modulation from A1/C1 neurons, via a continuous release of endogenous NA and activation of alpha2 adrenoceptors. Applying ACh at 25 microM activated the RRG but ACh had no effects at 50 microM. Applying the ACh receptor agonists nicotine and muscarine facilitated and depressed the RRG, respectively. After yohimbine pre-treatment that blocked the alpha2 facilitation, the nicotinic facilitation was not altered, the muscarinic depression was reversed and ACh 50 microM significantly facilitated the RRG. After L-tyrosine pre-treatment that potentiated the alpha2 facilitation, the muscarinic depression was enhanced. Thus, ACh regulates the RRG activity via nicotinic and muscarinic receptors, the muscarinic receptors interacting with alpha2 adrenoceptors

Reabilitação de conjuntos históricos rurais através do turismo : o roteiro Caminhos de Pedra em Bento Gonçalves / RS

O presente trabalho trata da reabilitação de conjuntos históricos rurais através do turismo, tendo como caso de estudo o roteiro Caminhos de Pedra em Bento Gonçalves/RS. A pesquisa dedica-se a avaliar a relação existente entre turismo e preservação do patrimônio, com atenção especial aos conjuntos históricos localizados em meio rural, cuja salvaguarda tem motivado atores sociais nas últimas décadas, porém ainda carente de estudos aprofundados. A análise abrange aspectos sociais, culturais, ambientais e econômicos, além de debruçar-se sobre o tema das intervenções arquitetônicas e suas alterações na paisagem e no edifício. A partir do reconhecimento e documentação da experiência, o estudo analisa o exemplo precursor na preservação do patrimônio arquitetônico em meio rural no sul do País, passível de ser enquadrado como bem sucedido. O trabalho também busca definir a importância do reuso como meio de preservação e valorização, bem como a influência da atividade comercial voltada ao turismo, responsável pela geração de renda e viabilização de ações de reabilitação e manutenção dos monumentos e bens em questão.This work is about rehabilitation of countryside historical buildings through tourism, using as a case study the route called Caminho de Pedras in the city of Bento Gonçalves/RS. This research aims to evaluate the relation between tourism and heritage preservation, with a special attention to the historical buildings located in a rural area, which protection has motivated social actors during the last decades, although still lacks deeper studies. The analysis approaches social, cultural, environmental and economic aspects, besides poring over the architectural interventions and their modifications to the scape and to the building. After recognizing and documenting the experience, the study considers the forerunner examples in the preservation of architectural heritage among rural areas in the southern part of the country, able to be considered successful. This research also looks for determining the importance of reuse as preservation and valorization mean, as well as the effect of tourist commercial activity, responsible for income generation and enabling rehabilitating and maintenance actions to the considered building