Colocalization of Oxtr with Prader-Willi syndrome transcripts in the trigeminal ganglion of neonatal mice.

Prader-Willi syndrome (PWS) is caused by deficient expression of the paternal copy of several contiguous genes on chromosome 15q11-q13 and affects multiple organ systems in the body, including the nervous system. Feeding and suckling deficits in infants with PWS are replaced with excessive feeding and obesity in childhood through adulthood. Clinical trials using intranasal oxytocin (OXT) show promise to improve feeding deficits in infants with PWS. The mechanism and location of action of exogenous OXT are unknown. We have recently shown in neonatal mice that OXT receptors (OXTR) are present in several regions of the face with direct roles in feeding. Here we show that the trigeminal ganglion, which provides sensory innervation to the face, is a rich source of Oxtr and a site of cellular co-expression with PWS gene transcripts. We also quantified OXTR ligand binding in mice deficient in Magel2, a PWS gene, within the trigeminal ganglion and regions that are anatomically relevant to feeding behavior and innervated by the trigeminal ganglion including the lateral periodontium, rostral periodontium, tongue, olfactory epithelium, whisker pads and brainstem. We found that peripheral OXTR ligand binding in the head is mostly intact in Magel2-deficient mice, although it is reduced in the lateral periodontium (gums) of neonatal Magel2-deficient mice compared to wild-type controls. These data suggest that OXT via orofacial OXTR may play a peripheral role to modulate sensory-motor reflexes necessary for suckling and may be part of the mechanism by which intranasal OXT shows promise for therapeutic benefit in PWS.

Oxytocin administration in neonates shapes hippocampal circuitry and restores social behavior in a mouse model of autism.

Oxytocin is an important regulator of the social brain. In some animal models of autism, notably in Magel2tm1.1Mus-deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mechanisms by which such oxytocin administration has long-term effects are known. Here, we aimed to clarify these oxytocin-dependent mechanisms, focusing on social memory performance. Using in situ hybridization (RNAscope), we have established that Magel2 and oxytocin receptor are co-expressed in the dentate gyrus and CA2/CA3 hippocampal regions involved in the circuitry underlying social memory. Then, we have shown that Magel2tm1.1Mus-deficient mice, evaluated in a three-chamber test, present a deficit in social memory. Next, in hippocampus, we conducted neuroanatomical and functional studies using immunostaining, oxytocin-binding experiments, ex vivo electrophysiological recordings, calcium imaging and biochemical studies. We demonstrated: an increase of the GABAergic activity of CA3-pyramidal cells associated with an increase in the quantity of oxytocin receptors and of somatostatin interneurons in both DG and CA2/CA3 regions. We also revealed a delay in the GABAergic development sequence in Magel2tm1.1Mus-deficient pups, linked to phosphorylation modifications of KCC2. Above all, we demonstrated the positive effects of subcutaneous administration of oxytocin in the mutant neonates, restoring hippocampal alterations and social memory at adulthood. Although clinical trials are debated, this study highlights the mechanisms by which peripheral oxytocin administration in neonates impacts the brain and demonstrates the therapeutic value of oxytocin to treat infants with autism spectrum disorders.

Stochastic loss of silencing of the imprinted Ndn/NDN allele, in a mouse model and humans with prader-willi syndrome, has functional consequences.

Genomic imprinting is a process that causes genes to be expressed from one allele only according to parental origin, the other allele being silent. Diseases can arise when the normally active alleles are not expressed. In this context, low level of expression of the normally silent alleles has been considered as genetic noise although such expression has never been further studied. Prader-Willi Syndrome (PWS) is a neurodevelopmental disease involving imprinted genes, including NDN, which are only expressed from the paternally inherited allele, with the maternally inherited allele silent. We present the first in-depth study of the low expression of a normally silent imprinted allele, in pathological context. Using a variety of qualitative and quantitative approaches and comparing wild-type, heterozygous and homozygous mice deleted for Ndn, we show that, in absence of the paternal Ndn allele, the maternal Ndn allele is expressed at an extremely low level with a high degree of non-genetic heterogeneity. The level of this expression is sex-dependent and shows transgenerational epigenetic inheritance. In about 50% of mutant mice, this expression reduces birth lethality and severity of the breathing deficiency, correlated with a reduction in the loss of serotonergic neurons. In wild-type brains, the maternal Ndn allele is never expressed. However, using several mouse models, we reveal a competition between non-imprinted Ndn promoters which results in monoallelic (paternal or maternal) Ndn expression, suggesting that Ndn allelic exclusion occurs in the absence of imprinting regulation. Importantly, specific expression of the maternal NDN allele is also detected in post-mortem brain samples of PWS individuals. Our data reveal an unexpected epigenetic flexibility of PWS imprinted genes that could be exploited to reactivate the functional but dormant maternal alleles in PWS. Overall our results reveal high non-genetic heterogeneity between genetically identical individuals that might underlie the variability of the phenotype.

Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.

Altered development of the human cerebral cortex can cause severe malformations with often intractable focal epileptic seizures and may participate in common pathologies, notably epilepsy. This raises important conceptual and therapeutic issues. Two missense mutations in the sushi repeat-containing protein SRPX2 had been previously identified in epileptic disorders with or without structural developmental alteration of the speech cortex. In the present study, we aimed to decipher the precise developmental role of SRPX2, to have a better knowledge on the consequences of its mutations, and to start addressing therapeutic issues through the design of an appropriate animal model. Using an in utero Srpx2 silencing approach, we show that SRPX2 influences neuronal migration in the developing rat cerebral cortex. Wild-type, but not the mutant human SRPX2 proteins, rescued the neuronal migration phenotype caused by Srpx2 silencing in utero, and increased alpha-tubulin acetylation. Following in utero Srpx2 silencing, spontaneous epileptiform activity was recorded post-natally. The neuronal migration defects and the post-natal epileptic consequences were prevented early in embryos by maternal administration of tubulin deacetylase inhibitor tubacin. Hence epileptiform manifestations of developmental origin could be prevented in utero, using a transient and drug-based therapeutic protocol.

Disengagement of somatostatin neurons from lateral septum circuitry by oxytocin and vasopressin restores social-fear extinction and suppresses aggression outbursts in Prader-Willi syndrome model.

Background: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown. Methods: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs. Results: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits. Conclusions: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.

Inactivation of Socs3 in the hypothalamus enhances the hindbrain response to endogenous satiety signals via oxytocin signaling.

Leptin is an adipocyte-derived hormone that controls energy balance by acting primarily in the CNS, but its action is lost in common forms of obesity due to central leptin resistance. One potential mechanism for such leptin resistance is an increased hypothalamic expression of Suppressor of cytokine signaling 3 (Socs3), a feedback inhibitor of the Jak-Stat pathway that prevents Stat3 activation. Ample studies have confirmed the important role of Socs3 in leptin resistance and obesity. However, the degree to which Socs3 participates in the regulation of energy homeostasis in nonobese conditions remains largely undetermined. In this study, using adult mice maintained under standard diet, we demonstrate that Socs3 deficiency in the mediobasal hypothalamus (MBH) reduces food intake, protects against body weight gain, and limits adiposity, suggesting that Socs3 is necessary for normal body weight maintenance. Mechanistically, MBH Socs3-deficient mice display increased hindbrain sensitivity to endogenous, meal-related satiety signals, mediated by oxytocin signaling. Thus, oxytocin signaling likely mediates the effect of hypothalamic leptin on satiety circuits of the caudal brainstem. This provides an anatomical substrate for the effect of leptin on meal size, and more generally, a mechanism for how the brain controls short-term food intake as a function of the energetic stores available in the organism to maintain energy homeostasis. Any dysfunction in this pathway could potentially lead to overeating and obesity.

Oxytocin receptors in the Magel2 mouse model of autism: Specific region, age, sex and oxytocin treatment effects.

The neurohormone oxytocin (OXT) has been implicated in the regulation of social behavior and is intensively investigated as a potential therapeutic treatment in neurodevelopmental disorders characterized by social deficits. In the Magel2-knockout (KO) mouse, a model of Schaaf-Yang Syndrome, an early postnatal administration of OXT rescued autistic-like behavior and cognition at adulthood, making this model relevant for understanding the actions of OXT in (re)programming postnatal brain development. The oxytocin receptor (OXTR), the main brain target of OXT, was dysregulated in the hippocampus of Magel2-KO adult males, and normalized upon OXT treatment at birth. Here we have analyzed male and female Magel2-KO brains at postnatal day 8 (P8) and at postnatal day 90 (P90), investigating age, genotype and OXT treatment effects on OXTR levels in several regions of the brain. We found that, at P8, male and female Magel2-KOs displayed a widespread, substantial, down-regulation of OXTR levels compared to wild type (WT) animals. Most intriguingly, the postnatal OXT treatment did not affect Magel2-KO OXTR levels at P8 and, consistently, did not rescue the ultrasonic vocalization deficits observed at this age. On the contrary, the postnatal OXT treatment reduced OXTR levels at P90 in male Magel2-KO in a region-specific way, restoring normal OXTR levels in regions where the Magel2-KO OXTR was upregulated (central amygdala, hippocampus and piriform cortex). Interestingly, Magel2-KO females, previously shown to lack the social deficits observed in Magel2-KO males, were characterized by a different trend in receptor expression compared to males; as a result, the dimorphic expression of OXTR observed in WT animals, with higher OXTR expression observed in females, was abolished in Magel2-KO mice. In conclusion, our data indicate that in Magel2-KO mice, OXTRs undergo region-specific modifications related to age, sex and postnatal OXT treatment. These results are instrumental to design precisely-timed OXT-based therapeutic strategies that, by acting at specific brain regions, could modify the outcome of social deficits in Schaaf-Yang Syndrome patients.

A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene.

The onset of feeding at birth is a vital step for the adaptation of the neonate to extra uterine life. Prader-Willi syndrome (PWS) is a complex neurogenetic disorder caused by the alteration of several imprinted contiguous genes including MAGEL2. PWS presents with various clinical manifestations, including poor suckling behaviour and feeding problems in neonates. Hypothalamic defects have been proposed, but the pathophysiological mechanisms remain poorly understood. Here, we report that a Magel2-deficient mouse with 50% neonatal mortality had an altered onset of suckling activity and subsequent impaired feeding, suggesting a role of MAGEL2 in the suckling deficit seen in PW newborns. The hypothalamus of Magel2 mutant neonates showed a significant reduction in oxytocin (OT). Furthermore, injection of a specific OT receptor antagonist in wild-type neonates recapitulated the feeding deficiency seen in Magel2 mutants, and a single injection of OT, 3-5 h after birth, rescued the phenotype of Magel2 mutant pups, allowing all of them to survive. Our study illustrates the crucial role of feeding onset behaviour after birth. We propose that OT supply might constitute a promising avenue for the treatment of feeding difficulties in PW neonates and potentially of other newborns with impaired feeding onset.

Necdin mediates skeletal muscle regeneration by promoting myoblast survival and differentiation.

Regeneration of muscle fibers that are lost during pathological muscle degeneration or after injuries is sustained by the production of new myofibers. An important cell type involved in muscle regeneration is the satellite cell. Necdin is a protein expressed in satellite cell-derived myogenic precursors during perinatal growth. However, its function in myogenesis is not known. We compare transgenic mice that overexpress necdin in skeletal muscle with both wild-type and necdin null mice. After muscle injury the necdin null mice show a considerable defect in muscle healing, whereas mice that overexpress necdin show a substantial increase in myofiber regeneration. We also find that in muscle, necdin increases myogenin expression, accelerates differentiation, and counteracts myoblast apoptosis. Collectively, these data clarify the function and mechanism of necdin in skeletal muscle and show the importance of necdin in muscle regeneration.

[As early as birth, oxytocin plays a key role in both food and social behavior]. / L'ocytocine, dès la naissance, conditionne le comportement alimentaire et social d'un individu.

Oxytocin (OT) is a neurohormone that regulates the so-called "social brain" and is mainly studied in adulthood. During postnatal development, the mechanisms by which the OT system structures various behaviors are little studied. Here we present the dynamic process of postnatal development of the OT system as well as the OT functions in the perinatal period that are essential for shaping social behaviors. Specifically, we discuss the role of OT, in the newborn, in integrating and adapting responses to early sensory stimuli and in stimulating suckling activity. Sensory dialogue and suckling are involved in mother-infant bonds and structure future social interactions. In rodents and humans, neurodevelopmental diseases with autism spectrum disorders (ASD), such as Prader-Willi and Schaaf-Yang syndromes, are associated with sensory, feeding and behavioral deficits in infancy. We propose that in early postnatal life, OT plays a key role in stimulating the maturation of neural networks controlling feeding behavior and early social interactions from birth. Administration of OT at birth improves sensory integration of environmental factors and the relationship with the mother as well as sucking activity as we have shown in mouse models and in babies with Prader-Willi syndrome. Long-term effects have also been observed on social and cognitive behavior. Therefore, early feeding difficulties might be an early predictive marker of ASD, and OT treatment a promising option to improve feeding behavior and, in the longer term, social behavioral problems.

Title: L'ocytocine, dès la naissance, conditionne le comportement alimentaire et social d'un individu. Abstract: L'ocytocine (OT) est une neurohormone qui, dans le cerveau, régule ce que l'on appelle le « cerveau social ¼ et dont l'étude est principalement conduite chez l'adulte. Au cours du développement postnatal, les mécanismes par lesquels le système OT structure divers comportements sont peu explorés. Nous présentons ici le processus dynamique du développement postnatal du système OT ainsi que ses rôles fonctionnels, en période périnatale, qui sont essentiels pour façonner les comportements sociaux. Nous abordons spécifiquement le rôle de l'OT chez le nouveau-né, qui permet d'intégrer et d'adapter des réponses aux premières stimulations sensorielles et qui stimule aussi l'activité de succion. Ce dialogue sensoriel et la tétée sont impliqués dans les liens mère-enfant et structurent les futures interactions sociales. Chez les rongeurs et chez l'homme, des maladies neuro-développementales avec des troubles du spectre autistique, comme les syndromes de Prader-Willi et de Schaaf-Yang, sont associées à des déficiences sensorielles, alimentaires et comportementales dans la petite enfance. Nous proposons qu'au début de la vie postnatale, l'OT joue un rôle clé dans la maturation des réseaux neuronaux contrôlant le comportement alimentaire et les premières interactions sociales. Une administration d'OT chez le nouveau-né améliore l'intégration sensorielle des facteurs environnementaux et la relation avec la mère ainsi que l'activité de succion comme nous l'avons montré chez des modèles de souris ainsi que chez des bébés atteints du syndrome de Prader-Willi. Des effets à long terme ont aussi été observés sur le comportement social et cognitif. Par conséquent, les difficultés précoces d'alimentation peuvent être un marqueur prédictif précoce des cas de troubles du spectre autistique (TSA) et l'administration exogène d'OT pourrait améliorer le comportement alimentaire et, à plus long terme, les troubles du comportement social.

Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies.

The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.

Neonatal oxytocin gives the tempo of social and feeding behaviors.

The nonapeptide oxytocin (OT) is a master regulator of the social brain in early infancy, adolescence, and adult life. Here, we review the postnatal dynamic development of OT-system as well as early-life OT functions that are essential for shaping social behaviors. We specifically address the role of OT in neonates, focusing on its role in modulating/adapting sensory input and feeding behavior; both processes are involved in the establishing mother-infant bond, a crucial event for structuring all future social interactions. In patients and rodent models of Prader-Willi and Schaaf-Yang syndromes, two neurodevelopmental diseases characterized by autism-related features, sensory impairments, and feeding difficulties in early infancy are linked to an alteration of OT-system. Successful preclinical studies in mice and a phase I/II clinical trial in Prader-Willi babies constitute a proof of concept that OT-treatment in early life not only improves suckling deficit but has also a positive long-term effect on learning and social behavior. We propose that in early postnatal life, OT plays a pivotal role in stimulating and coordinating the maturation of neuronal networks controlling feeding behavior and the first social interactions. Consequently, OT therapy might be considered to improve feeding behavior and, all over the life, social cognition, and learning capabilities.

Modulation of the thermosensory system by oxytocin.

Oxytocin (OT) is a neurohormone involved early in neurodevelopment and is implicated in multiple functions, including sensory modulation. Evidence of such modulation has been observed for different sensory modalities in both healthy and pathological conditions. This review summarizes the pleiotropic modulation that OT can exercise on an often overlooked sensory system: thermosensation. This system allows us to sense temperature variations and compensate for the variation to maintain a stable core body temperature. Oxytocin modulates autonomic and behavioral mechanisms underlying thermoregulation at both central and peripheral levels. Hyposensitivity or hypersensitivity for different sensory modalities, including thermosensitivity, is a common feature in autism spectrum disorder (ASD), recapitulated in several ASD mouse models. These sensory dysregulations occur early in post-natal development and are correlated with dysregulation of the oxytocinergic system. In this study, we discussed the potential link between thermosensory atypia and the dysregulation of the oxytocinergic system in ASD.

Early life oxytocin treatment improves thermo-sensory reactivity and maternal behavior in neonates lacking the autism-associated gene Magel2.

Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage and rescued by therapeutic strategy are fairly uninvestigated. Here we found that under cool environment neonatal mice lacking the autism-associated gene Magel2 present pup calls hypo-reactivity and are retrieved with delay by their wild-type dam. This neonatal atypical sensory reactivity to cool stimuli was not associated with autonomic thermoregulatory alteration but with a deficit of the oxytocinergic system. Indeed, we show in control neonates that pharmacogenetic inactivation of hypothalamic oxytocin neurons mimicked atypical thermosensory reactivity found in Magel2 mutants. Furthermore, pharmacological intranasal administration of oxytocin to Magel2 neonates was able to rescue both the atypical thermosensory response and the maternal pup retrieval. This preclinical study establishes for the first-time early life impairments in thermosensory integration and suggest a therapeutic potential benefit of intranasal oxytocin treatment on neonatal atypical sensory reactivity for autism.

The impact of oxytocin on neurite outgrowth and synaptic proteins in Magel2-deficient mice.

Oxytocin contributes to the regulation of cytoskeletal and synaptic proteins and could, therefore, affect the mechanisms of neurodevelopmental disorders, including autism. Both the Prader-Willi syndrome and Schaaf-Yang syndrome exhibit autistic symptoms involving the MAGEL2 gene. Magel2-deficient mice show a deficit in social behavior that is rescued following the postnatal administration of oxytocin. Here, in Magel2-deficient mice, we showed that the neurite outgrowth of primary cultures of immature hippocampal neurons is reduced. Treatment with oxytocin reversed this abnormality. In the hippocampus of Magel2-deficient pups, we further demonstrated that several transcripts of neurite outgrowth-associated proteins, synaptic vesicle proteins, and cell-adhesion molecules are decreased. In the juvenile stage, when neurons are mature, normalization or even overexpression of most of these markers was observed, suggesting a delay in the neuronal maturation of Magel2-deficient pups. Moreover, we found reduced transcripts of the excitatory postsynaptic marker, Psd95 in the hippocampus and we observed a decrease of PSD95/VGLUT2 colocalization in the hippocampal CA1 and CA3 regions in Magel2-deficient mice, indicating a defect in glutamatergic synapses. Postnatal administration of oxytocin upregulated postsynaptic transcripts in pups; however, it did not restore the level of markers of glutamatergic synapses in Magel2-deficient mice. Overall, Magel2 deficiency leads to abnormal neurite outgrowth and reduced glutamatergic synapses during development, suggesting abnormal neuronal maturation. Oxytocin stimulates the expression of numerous genes involved in neurite outgrowth and synapse formation in early development stages. Postnatal oxytocin administration has a strong effect on development that should be considered for certain neuropsychiatric conditions in infancy.

Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model.

Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.

ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs.

Posttranscriptional, site-specific adenosine to inosine (A-to-I) base conversions, designated as RNA editing, play significant roles in generating diversity of gene expression. However, little is known about how and in which cellular compartments RNA editing is controlled. Interestingly, the two enzymes that catalyze RNA editing, adenosine deaminases that act on RNA (ADAR) 1 and 2, have recently been demonstrated to dynamically associate with the nucleolus. Moreover, we have identified a brain-specific small RNA, termed MBII-52, which was predicted to function as a nucleolar C/D RNA, thereby targeting an A-to-I editing site (C-site) within the 5-HT2C serotonin receptor pre-mRNA for 2'-O-methylation. Through the subcellular targeting of minigenes that contain natural editing sites, we show that ADAR2- but not ADAR1-mediated RNA editing occurs in the nucleolus. We also demonstrate that MBII-52 forms a bona fide small nucleolar ribonucleoprotein particle that specifically decreases the efficiency of RNA editing by ADAR2 at the targeted C-site. Our data are consistent with a model in which C/D small nucleolar RNA might play a role in the regulation of RNA editing.

Necdin plays a role in the serotonergic modulation of the mouse respiratory network: implication for Prader-Willi syndrome.

Prader-Willi syndrome is a neurogenetic disease resulting from the absence of paternal expression of several imprinted genes, including NECDIN. Prader-Willi children and adults have severe breathing defects with irregular rhythm, frequent sleep apneas, and blunted respiratory regulations. For the first time, we show that Prader-Willi infants have sleep apneas already present at birth. In parallel, in wild-type and Necdin-deficient mice, we studied the respiratory system with in vivo plethysmography, in vitro electrophysiology, and pharmacology. Because serotonin is known to contribute to CNS development and to affect maturation and function of the brainstem respiratory network, we also investigated the serotonergic system with HPLC, immunohistochemistry, Rabies virus tracing approaches, and primary culture experiments. We report first that Necdin-deficiency in mice induces central respiratory deficits reminiscent of Prader-Willi syndrome (irregular rhythm, frequent apneas, and blunted respiratory regulations), second that Necdin is expressed by medullary serotonergic neurons, and third that Necdin deficiency alters the serotonergic metabolism, the morphology of serotonin vesicles in medullary serotonergic neurons but not the number of these cells. We also show that Necdin deficiency in neonatal mice alters the serotonergic modulation of the respiratory rhythm generator. Thus, we propose that the lack of Necdin expression induces perinatal serotonergic alterations that affect the maturation and function of the respiratory network, inducing breathing deficits in mice and probably in Prader-Willi patients.

Necdin gene, respiratory disturbances and Prader-Willi syndrome.

Prader-Willi Syndrome (PWS) is a complex neurogenetic disease with various symptoms, including breathing deficits and possible alteration of serotonin (5HT) metabolism. As PWS results from the absence of paternal expression of several imprinted genes among which NECDIN (Ndn), we examined whether Ndn deficiency in mice induced breathing and 5HT deficits. In vivo, Ndn-deficient mice (Ndn-/-) had irregular breathing, severe apneas and blunted respiratory response to hypoxia. In vitro, medullary preparations from Ndn-/- neonates produced a respiratory-like rhythm that was highly irregular, frequently interrupted and abnormally regulated by central hypoxia. In wild type (wt) and Ndn-/- neonates, immunohistofluorescence and biochemistry revealed that medullary 5HT neurons expressed Ndn in wt and that the medulla contained abnormally high levels of 5HT in Ndn-/-. Thus, our preliminary results fully confirm a primary role of Ndn in PWS, revealing that Ndn-deficiency in mice induces respiratory and 5HT alterations reminiscent of PWS.

Wired for eating: how is an active feeding circuitry established in the postnatal brain?

From birth, mammals have to find food and maximize caloric intake to ensure growth and survival. Suckling must be initiated quickly after birth and then maintained and controlled until weaning. It is a complex process involving interactions between sensory and motor neuronal pathways. Meanwhile, the control of food intake and energy homeostasis is progressively established via the development of hypothalamic circuits. The development of these circuits is influenced by hormonal and nutritional signals and can be disturbed in a variety of developmental disorders leading to long-term metabolic, behavioral and cognitive dysfunctions. This review summarizes our current knowledge of the neuronal circuits involved in early postnatal feeding processes.