Jean Mariani - Academia.edu (original) (raw)

Papers by Jean Mariani

Experimental Gerontology, Oct 1, 2007

In Alzheimer's disease there is an increased production of the toxic b-amyloid peptides (Ab), esp... more In Alzheimer's disease there is an increased production of the toxic b-amyloid peptides (Ab), especially the longer forms such as Ab(1-42). Using the patch-clamp technique we have studied the contribution of early pro-inflammatory processes to the acute effects of 1 lM Ab(1-42) on the parallel fiber EPSC (PF-EPSC) of Purkinje cells in cerebellar slices. Ab(1-42) induces a decrease in the PF-EPSC amplitude. This decrease is accompanied by a decrease in the frequency and amplitude of the miniature EPSCs, suggesting that Ab acts at both pre-and post-synaptic sites. In the presence of L-NAME, a nitric oxide synthase inhibitor, the effects of Ab were partially blocked. The frequency of mEPSCs was unchanged while Ab still reduced the mEPSCs amplitude. The anti-inflammatory agent flurbiprofen blocked the depressant action of Ab on the mEPSCs amplitude but not its effect on mEPSCs frequency. Both a p38 inhibitor (SB203580) and a JNK inhibitor (SP600125) reverse the effects of Ab as an increase in the mEPSCs frequency and amplitude was observed. This study provides evidence that the Ab-induced depression of the PF-EPSCs was mediated via an activation of JNK and p38 and by the action of NO and raises the possibility of the involvement of an early pro-inflammatory process.

bioRxiv (Cold Spring Harbor Laboratory), Jan 9, 2021

Synaptic transmission, connectivity, and dendritic morphology mature in parallel during brain dev... more Synaptic transmission, connectivity, and dendritic morphology mature in parallel during brain development and are often disrupted in neurodevelopmental disorders. Yet how these changes influence the neuronal computations necessary for normal brain function are not well understood. To identify cellular mechanisms underlying the maturation of synaptic integration in interneurons, we combined patch-clamp recordings of excitatory inputs in mouse cerebellar stellate cells (SCs), three-dimensional reconstruction of SC morphology with excitatory synapse location, and biophysical modeling. We found that postnatal maturation of postsynaptic strength was homogeneously reduced along the somatodendritic axis, but dendritic integration was always sublinear. However, dendritic branching increased without changes in synapse density, leading to a substantial gain in distal inputs. Thus, changes in synapse distribution, rather than dendrite cable properties, are the dominant mechanism underlying the maturation of neuronal computation. These mechanisms favor the emergence of a spatially compartmentalized two-stage integration model promoting location-dependent integration within dendritic subunits.

Médecine du sommeil, Mar 1, 2017

Déclaration de liens d'intérêts Investigateur Tasimelteon chez les non-voyants en libre cours, Co... more Déclaration de liens d'intérêts Investigateur Tasimelteon chez les non-voyants en libre cours, Conseil IRIS pour agomelatine, Investigateur Bioprojet Pitolosam, Etudes de recherche sponsorisées par Les Gueules Cassés et Fondation Vinci pour une Conduite Responsable.

Alzheimers & Dementia, Jul 1, 2011

Proceedings of the National Academy of Sciences of the United States of America, Aug 18, 2009

During developmental synaptogenesis, the pre-and postsynaptic cells undergo specific interactions... more During developmental synaptogenesis, the pre-and postsynaptic cells undergo specific interactions that lead to the establishment of the mature circuit. We have studied the roles of the pre-and postsynaptic cells in establishing this mature innervation by using an in vitro model of synaptic development. We describe climbing fiber (CF)-Purkinje cell (PC) synaptogenesis in cultured mouse hindbrain explants and show that synaptic competition occurs during early development in vitro. By manipulating the maturation stage of each of the synaptic partners in a coculture experimental paradigm, we found that multi-innervation does not occur when both synaptic partners are mature and have already experienced synapse elimination; in contrast, mature PCs can be multi-innervated when they have never experienced synapse elimination and/or when CFs are immature. However in these cases, the normal process of synapse elimination is impaired. These results show that CF-synapse elimination occurs only during a PC-dependant critical period and triggers indelible signals that prevent synapse competition in the mature system.

Neural Development, 2010

Background: The active form (T 3) of thyroid hormone (TH) controls critical aspects of cerebellar... more Background: The active form (T 3) of thyroid hormone (TH) controls critical aspects of cerebellar development, such as migration of postmitotic neurons and terminal dendritic differentiation of Purkinje cells. The effects of T 3 on early dendritic differentiation are poorly understood. Results: In this study, we have analyzed the influence of T 3 on the progression of the early steps of Purkinje cell dendritic differentiation in postnatal day 0 organotypic cerebellar cultures. These steps include, successively, regression of immature neuritic processes, a stellate cell stage, and the extension of several long and mature perisomatic protrusions before the growth of the ultimate dendritic tree. We also studied the involvement of RORα, a nuclear receptor controlling early Purkinje cell dendritic differentiation. We show that T 3 treatment leads to an accelerated progression of the early steps of dendritic differentiation in culture, together with an increased expression of RORα (mRNA and protein) in both Purkinje cells and interneurons. Finally, we show that T 3 failed to promote early dendritic differentiation in staggerer RORα-deficient Purkinje cells. Conclusions: Our results demonstrate that T 3 action on the early Purkinje cell dendritic differentiation process is mediated by RORα.

The Journal of Neuroscience, Feb 1, 2006

Dendritic differentiation involves both regressive and growth events. The mechanisms controlling ... more Dendritic differentiation involves both regressive and growth events. The mechanisms controlling the regressive events are poorly understood. This study is aimed at determining the role of the nuclear receptor retinoid-related orphan receptor ␣ (ROR␣) in Purkinje cell (PC) dendritic differentiation in organotypic cultures. As observed in vivo, in these cultures, fusiform PCs with embryonic bipolar shape undergo regression before the outgrowth of the ultimate dendritic tree. We show that lentiviral-mediated hROR␣1 overexpression in fusiform PCs leads to a cell-autonomous accelerated progression of dendritic differentiation. In addition, ROR␣ is necessary for the PC regressive events: whereas staggerer ROR␣-deficient PCs remain in the embryonic fusiform stage, replacement of hROR␣1 restores normal dendritogenesis. These results demonstrate that ROR␣ expression in fusiform PCs is crucial for the dendritic regression and progression of the following step of extension of dendritic processes. However, it does not seem to participate to the last stage of dendritic growth. This study identifies ROR␣ as a nuclear receptor crucial for the control of dendritic remodeling during development.

HAL (Le Centre pour la Communication Scientifique Directe), 2006

RORα (Retinoid-related Orphan Receptor) is a transcription factor belonging to the superfamily of... more RORα (Retinoid-related Orphan Receptor) is a transcription factor belonging to the superfamily of nuclear receptors. The spontaneous staggerer (sg) mutation, which consists of a deletion in the Rora ge ne, has been shown to cause the loss of function of the RORα protein. The total loss of RORα expression leads to cerebellar developmental defects, particularly to a dramatic decreased survival of Purkinje cells and an early block in the differentiation process. This review focuses on recent studies which position RORα as a pivotal factor controlling Purkinje cell survival and differentiation, from development to ageing.

The utility of EEG in Alzheimer’s disease (AD) research has been demonstrated over several decade... more The utility of EEG in Alzheimer’s disease (AD) research has been demonstrated over several decades in numerous studies. EEG markers have been employed successfully to investigate AD-related alterations in prodromal AD and AD dementia. Preclinical AD is a recent concept and a novel target for clinical research. This project tackles two issues: first, AD prediction at the preclinical sta ge, by exploiting the multimodal INSIGHT-preAD database, acquired at the Pitie-Salpetriere Hospital; second, an automatic AD diagnosis in a differential framework, by exploiting another large-scale EEG database, acquired at Charles-Foix Hospital. In this project, we will investigate AD predictors at preclinical stage, using EEG data of only subjective Memory Complainers in order to establish a cognitive profiling of elderly at-risk. We will also identify EEG markers for AD detection at early stages in a di fferential diagnosis context. The correlation between EEG markers and clinical biomarkers will b...

Essentials of Cerebellum and Cerebellar Disorders, 2016

The staggerer mutant mouse carries a spontaneous mutation in the ligand-binding domain of the ror... more The staggerer mutant mouse carries a spontaneous mutation in the ligand-binding domain of the rora gene. RORα is expressed in many tissues and its loss leads to diverse abnormalities. In the cerebellum of staggerer mice, there is severe early degeneration of Purkinje cells and associated death of their afferent neurons (granule and olivary neurons). Thus staggerer mice have atrophic cerebella and associated severe ataxia. In contrast, although heterozygote staggerer mice develop apparently normally, there is premature Purkinje cell atrophy and death in adulthood. Given that recent links have been demonstrated between RORα and spinocerebellar ataxia and autism spectrum disorders, the staggerer mouse is a particularly interesting model for cerebellar pathologies.

Brain Research, Nov 1, 1975

ABSTRACT

Journal of Neurogenetics, 1990

Staggerer (sg) is an autosomal recessive mutation in mouse that causes severe cerebellar atrophy.... more Staggerer (sg) is an autosomal recessive mutation in mouse that causes severe cerebellar atrophy. In this mutant, the Purkinje cell (PC) number is reduced by about 75% and the remaining Purkinje cells have a reduced dendritic arbor and an ectopic location. Previous analysis of staggerer chimeras has demonstrated that the Purkinje cell phenotypes are all direct consequences of the cell-autonomous action of the staggerer gene. The two major afferents to the Purkinje cell are also affected. Virtually all of the granule cells die by the end of the first postnatal month. This death, however has been shown to be an indirect consequence of mutant gene action. The second major afferent system is from the cells of the inferior olive that projects to the main trunks of the Purkinje cell dendrite via the climbing fiber system. Quantitative studies of cell number in the inferior olive have shown that the number of cells is reduced by about 62% in adult sg/sg mutants. We report here the results of our quantitative analysis of three staggerer chimeras. beta-glucuronidase activity was used as an independent cell marker. Our findings demonstrate that inferior olive cell death in staggerer mutant mice is an indirect effect of staggerer gene action. Thus as for the granule cells, the loss of olivary neurons most likely results from a target related cell death.

Developmental Brain Research, 1997

The cerebellum of the heterozygous qrsg staggerer mutant mouse has recently been proposed as a mo... more The cerebellum of the heterozygous qrsg staggerer mutant mouse has recently been proposed as a model system in which to study the genetic contribution to the normal process of central nervous system aging since there is significant loss of neurons from 3 to 12 Ž Ž. .

Frontiers in Behavioral Neuroscience, 2013

Episodic memory refers to the recollection of personal experiences that contain information on wh... more Episodic memory refers to the recollection of personal experiences that contain information on what has happened and also where and when these events took place. Episodic memory function is extremely sensitive to cerebral aging and neurodegerative diseases. We examined episodic memory performance with a novel test in young (N = 17, age: 21-45), middle-aged (N = 16, age: 48-62) and aged but otherwise healthy participants (N = 8, age: 71-83) along with measurements of trait and state anxiety. As expected we found significantly impaired episodic memory performance in the aged group as compared to the young group. The aged group also showed impaired working memory performance as well as significantly decreased levels of trait anxiety. No significant correlation between the total episodic memory and trait or state anxiety scores was found. The present results show an age-dependent episodic memory decline along with lower trait anxiety in the aged group. Yet, it still remains to be determined whether this difference in anxiety is related to the impaired episodic memory performance in the aged group.

Developmental Brain Research, Jun 1, 1992

Staggerer is a neurological mutation of mice that causes a severe ataxia correlated with digenesi... more Staggerer is a neurological mutation of mice that causes a severe ataxia correlated with digenesis of the cerebellar cortex. The Purkinje cell population in the homozygous mutant is reduced in size with a near total atrophy of dendritic structure. Further, the cells are ectopic and are reduced in number by about 75%. All of these phenotypes have been shown to be direct effects of the staggerer gene on the Purkinje cell itself. As an indirect consequence of gene action, virtually all of the cerebellar granule cells die as do 60% of the cells of the inferior olive. The mutation is described as recessive because of the heterozygote, +/sg, is behaviorally normal and the mature cerebellum shows none of the defects described in the homozygous mutant. We report here that, as the +/sg mouse advances in age, a syndrome of cell losses is observed. While these losses are not as severe as in the homozygote, by 12 months of age 35% of the Purkinje cells are gone, as are 35% of the granule cells and 40% of the cells in the inferior olive. We propose that these results illustrate a synergy between the aging process and the heterozygous genotype. Neither alone is sufficient to cause the cell loss. This interaction suggests that the +/sg represents a new model for the genetic contribution to regressive CNS changes during aging.

Developmental Brain Research, Oct 1, 1996

During a defined critical period of development, if the target of a neuronal population is remove... more During a defined critical period of development, if the target of a neuronal population is removed, there is a massive decrease in the number of neurons that survive into adulthood. Previous studies have found that source neuron number is a strictly linear function of target size. The current work extends these observations to the inferior olive-+ Purkinje cell projection. Three distinct model systems have been used: (i) lurcher ~ wild-type aggregation chimeras, (ii) staggerer~ wild-type chimeras and (iii) naturally occurring polymorphisms in Purkinje cell number found in different inbred mouse strains. Total neuron numbers were counted in the inferior olive and plotted as a function of the number of Purkinje cells in the contralateral cerebellar cortex. In lurcher mutants and chimeras, the relationship between these values is well described by a straight line. This suggests that, like the granule ~ Purkinje cell circuit, the olive ~ Purkinje cell circuit uses a linear algorithm to achieve a numerical balance. The results from the two other model systems were not as clear cut. In the staggerer chimeras, we found only a rough correlation between neuron and target numbers and in the inbred strains there was no discernible relationship at all. These findings indicate that in the final analysis, there are multiple factors involved in the determination of the number of olive cells surviving into adulthood. The potential contribution of sustaining collaterals and afferent inputs is discussed as well as the possible existence of different subcircuits of olivocerebellar connections, each with its own numerical matching function.

Brain Research, Nov 1, 2009

Hippocampal dentate gyrus possesses an exceptional capacity of adaptation to ischemic insults. Re... more Hippocampal dentate gyrus possesses an exceptional capacity of adaptation to ischemic insults. Recently, using a transient global ischemic model in the adult rat, we identified a neuroprotective signalling cascade in the dentate gyrus involving calcium/calmodulindependent protein kinase IV (CaMKIV), cyclic AMP response element (CRE)-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), a major regulator of survival. We have shown that intracerebroventricular injections of anti-BDNF and anti-CREB are sufficient to cause substantial tissular damages and apoptotic deaths in late periods (48-72 h) after ischemia. Herein, we provide immunohistochemical and biochemical evidence that antibody-induced impairment of the protective CaMKIV/CREB/BDNF pathway induces an apparent duality of response in the dentate gyrus. The experimental protocol is performed as follows: (a) rats are anesthetized and vertebral arteries are occluded by electrocauterization; (b) on the following day, transient global ischemia is produced by occlusion of carotid arteries for 25 min; (c) finally, rats are infused with the pharmacologic agents into the left cerebral ventricle and then perfusion-fixed at different time points after ischemia for immunohistochemical and immunoblotting analyses. After infusion with anti-CaMKIV, phosphorylation of mitogen-activated protein kinases (MAPK) MKK3, MKK6 and p38 and phospho-acetylation of histone H3 occur at 6 h after ischemia without presence of any caspase-9 activation and cellular injuries. In contrast, infusion of anti-BDNF or anti-CREB surprisingly results in a remarkable stimulation of casein kinase 2 (CK2) and caspase-9 activities at 48-72 h post-insult. This is accompanied by the disappearance of phosphorylation of MKK(3/6) and p38 and phospho-acetylation of histone H3. These results suggest that: (1) activation of a MKK(3/6

Médecine du sommeil, 2015

Proportions of reversible and irreversible magnetization processes in the overall magnetization p... more Proportions of reversible and irreversible magnetization processes in the overall magnetization process were studied in a complex view of magnetic, thermal and electrical properties of iron-phenolphormaldehyde resin composites. They were determined experimentally at different values of magnetic induction along the initial curve. The results of total, differential, reversible and irreversible permeability measurement as well as the analysis of DC energy losses revealed the same tendencies: The numbers of movable domain walls (determining the extent of reversible processes) depend on the magnetic particle size and the resin content through the demagnetizing fields produced by the particle surfaces, lowering the interaction between particles. Thermal diffusivity was compared with Hashin-Shtrikman model indicating good insulation of particles.

Circulation Research, Dec 7, 2001

Ror␣ is an orphan nuclear receptor. In homozygous staggerer mutant mice (Rora sg/sg), a deletion ... more Ror␣ is an orphan nuclear receptor. In homozygous staggerer mutant mice (Rora sg/sg), a deletion within the Rora gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of ischemia-induced angiogenesis, we studied the role of Ror␣ in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Rora ϩ/ϩ and Rora sg/sg mice. After 3 and 28 days, angiogenesis was evaluated by microangiography, measurement of capillary density using immunohistochemistry (anti-CD31), and measurement of blood flow by laser Doppler imaging. At day 3, angiographic score and blood flow were similar in Rora sg/sg mice and in Rora ϩ/ϩ littermates. Conversely, at day 28, Rora sg/sg mice showed a significant 2-fold increase in angiographic score and a 3-fold increase in capillary density within the ischemic hindlimb compared with control. Functionally, this coincided with a significant rise in leg perfusion in Rora sg/sg mice (0.83Ϯ0.05 for ischemic/nonischemic leg perfusion ratio) compared with Ror ϩ/ϩ mice (0.66Ϯ0.04, PϽ0.05). In addition, more extensive angiogenesis in Rora sg/sg mice correlated with an increased expression of eNOS protein by 83Ϯ12% and 71Ϯ24% at 3 and 28 days, respectively (PϽ0.05), whereas the level of the antiangiogenic cytokine IL-12 was significantly reduced by 38Ϯ10% at day 28 (PϽ0.05). Conversely, no changes in VEGF expression were observed. Our study identifies for the first time a new role for Ror␣ as a potent negative regulator of ischemia-induced angiogenesis.