-
Patricia Carrasco, Ignasi Sahún,
Jerome McDonald,
Sara Ramírez,
Jordi Jacas,
Esther Gratacós,
Adriana Y Sierra,
Dolors Serra,
Laura Herrero,
Amparo Acker-Palmer,
Fausto G Hegardt,
Mara Dierssen,
Núria Casals
[show abstract]
[hide abstract]
ABSTRACT: The brain-specific isoform carnitine palmitoyltransferase 1C (CPT1C) has been implicated in the hypothalamic regulation of food intake and energy homeostasis. Nevertheless, its molecular function is not completely understood, and its role in other brain areas is unknown. We demonstrate that CPT1C is expressed in pyramidal neurons of the hippocampus and is located in the endoplasmic reticulum throughout the neuron, even inside dendritic spines. We used molecular, cellular, and behavioral approaches to determine CPT1C function. First, we analyzed the implication of CPT1C in ceramide metabolism. CPT1C overexpression in primary hippocampal cultured neurons increased ceramide levels, whereas in CPT1C-deficient neurons, ceramide levels were diminished. Correspondingly, CPT1C knock-out (KO) mice showed reduced ceramide levels in the hippocampus. At the cellular level, CPT1C deficiency altered dendritic spine morphology by increasing immature filopodia and reducing mature mushroom and stubby spines. Total protrusion density and spine head area in mature spines were unaffected. Treatment of cultured neurons with exogenous ceramide reverted the KO phenotype, as did ectopic overexpression of CPT1C, indicating that CPT1C regulation of spine maturation is mediated by ceramide. To study the repercussions of the KO phenotype on cognition, we performed the hippocampus-dependent Morris water maze test on mice. Results show that CPT1C deficiency strongly impairs spatial learning. All of these results demonstrate that CPT1C regulates the levels of ceramide in the endoplasmic reticulum of hippocampal neurons, and this is a relevant mechanism for the correct maturation of dendritic spines and for proper spatial learning.
Journal of Biological Chemistry 04/2012; 287(25):21224-32. · 4.77 Impact Factor
-
Cátia M Teixeira,
Eduardo D Martín, Ignasi Sahún,
Nuria Masachs,
Lluís Pujadas,
André Corvelo,
Carles Bosch,
Daniela Rossi,
Albert Martinez,
Rafael Maldonado,
Mara Dierssen,
Eduardo Soriano
[show abstract]
[hide abstract]
ABSTRACT: Despite the impact of schizophrenia and mood disorders, which in extreme cases can lead to death, recent decades have brought little progress in the development of new treatments. Recent studies have shown that Reelin, an extracellular protein that is critical for neuronal development, is reduced in schizophrenia and bipolar disorder patients. However, data on a causal or protective role of Reelin in psychiatric diseases is scarce. In order to study the direct influence of Reelin's levels on behavior, we subjected two mouse lines, in which Reelin levels are either reduced (Reelin heterozygous mice) or increased (Reelin overexpressing mice), to a battery of behavioral tests: open-field, black-white box, novelty-suppressed-feeding, forced-swim-test, chronic corticosterone treatment followed by forced-swim-test, cocaine sensitization and pre-pulse inhibition (PPI) deficits induced by N-methyl-D-aspartate (NMDA) antagonists. These tests were designed to model some aspects of psychiatric disorders such as schizophrenia, mood, and anxiety disorders. We found no differences between Reeler heterozygous mice and their wild-type littermates. However, Reelin overexpression in the mouse forebrain reduced the time spent floating in the forced-swim-test in mice subjected to chronic corticosterone treatment, reduced behavioral sensitization to cocaine, and reduced PPI deficits induced by a NMDA antagonist. In addition, we demonstrate that while stress increased NMDA NR2B-mediated synaptic transmission, known to be implicated in depression, Reelin overexpression significantly reduced it. Together, these results point to the Reelin signaling pathway as a relevant drug target for the treatment of a range of psychiatric disorders.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2011; 36(12):2395-405. · 6.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The increase in the incidence of obesity and eating disorders has promoted research aimed at understanding the aetiology of abnormal eating behaviours. Apart from metabolic factors, obesity is caused by overeating. Clinical reports have led to the suggestion that some individuals may develop addictive-like behaviours when consuming palatable foods, and compulsive eating plays a similar dominant role in obesity as compulsive drug taking does in drug addiction. The progress made in the development of treatment strategies for obesity is limited, in part, because the physiological and neurological causes and consequences of compulsive eating behaviour are not clearly understood and cannot readily be studied in human subjects. We have developed experimental approaches that reflect the functioning of the components of eating control, including compulsive food taking in rats. Rats that are given free choice between standard chow and a palatable, chocolate-containing 'Cafeteria Diet' (CD) develop distinct signs of compulsive food taking that appear at an early stage. These include the inability to adapt intake behaviour in periods of limited or bitter-tasting CD access, continued food intake during resting phases and changes in fine structure of feeding (duration, distribution and recurrence of feeding bouts). The model will help examine the neurobiological underpinnings of compulsive food seeking and food taking and provides a possibility to study the effects of novel anti-obesity compounds on compulsive eating and other components of food-taking behaviour in detail. For future use of genetic models, the possibility of a transfer to a mouse was discussed.
Addiction Biology 10/2009; 14(4):373-83. · 4.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The increase in the incidence of obesity and eating disorders has promoted research aimed at understanding the aetiology of abnormal eating behaviours. Apart from metabolic factors, obesity is caused by overeating. Clinical reports have led to the suggestion that some individuals may develop addictive-like behaviours when consuming palatable foods, and compulsive eating plays a similar dominant role in obesity as compulsive drug taking does in drug addiction. The progress made in the development of treatment strategies for obesity is limited, in part, because the physiological and neurological causes and consequences of compulsive eating behaviour are not clearly understood and cannot readily be studied in human subjects. We have developed experimental approaches that reflect the functioning of the components of eating control, including compulsive food taking in rats. Rats that are given free choice between standard chow and a palatable, chocolate-containing ‘Cafeteria Diet’ (CD) develop distinct signs of compulsive food taking that appear at an early stage. These include the inability to adapt intake behaviour in periods of limited or bitter-tasting CD access, continued food intake during resting phases and changes in fine structure of feeding (duration, distribution and recurrence of feeding bouts). The model will help examine the neurobiological underpinnings of compulsive food seeking and food taking and provides a possibility to study the effects of novel anti-obesity compounds on compulsive eating and other components of food-taking behaviour in detail. For future use of genetic models, the possibility of a transfer to a mouse was discussed.
Addiction Biology 09/2009; 14(4):373 - 383. · 4.83 Impact Factor
-
Patricia Lopes Pereira,
Laetitia Magnol, Ignasi Sahún,
Véronique Brault,
Arnaud Duchon,
Paola Prandini,
Agnès Gruart,
Jean-Charles Bizot,
Bernadette Chadefaux-Vekemans,
Samuel Deutsch,
Fabrice Trovero,
José María Delgado-García,
Stylianos E Antonarakis,
Mara Dierssen,
Yann Herault
[show abstract]
[hide abstract]
ABSTRACT: Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1-U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1-U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1-U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1-U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory.
Human Molecular Genetics 09/2009; 18(24):4756-69. · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Genetic-dissection studies carried out with Down syndrome (DS) murine models point to the critical contribution of Dyrk1A overexpression to the motor abnormalities and cognitive deficits displayed in DS individuals. In the present study we have used a murine model overexpressing Dyrk1A (TgDyrk1A mice) to evaluate whether functional CNS defects could be corrected with an inhibitory RNA against Dyrk1A, delivered by bilateral intrastriatal injections of adeno-associated virus type 2 (AAVshDyrk1A). We report that AAVshDyrk1A efficiently transduced HEK293 cells and primary neuronal cultures, triggering the specific inhibition of Dyrk1A expression. Injecting the vector into the striata of TgDyrk1A mice resulted in a restricted, long-term transduction of the striatum. This gene therapy was found to be devoid of toxicity and succeeded in normalizing Dyrk1A protein levels in TgDyrk1A mice. Importantly, the behavioral studies of the adult TgDyrk1A mice treated showed a reversal of corticostriatal-dependent phenotypes, as revealed by the attenuation of their hyperactive behavior, the restoration of motor-coordination defects, and an improvement in sensorimotor gating. Taken together, the data demonstrate that normalizing Dyrk1A gene expression in the striatum of adult TgDyrk1A mice, by means of AAVshRNA, clearly reverses motor impairment. Furthermore, these results identify Dyrk1A as a potential target for therapy in DS.
The American Journal of Human Genetics 11/2008; 83(4):479-88. · 10.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Neurotrophins and their cognate receptors might serve as feedback regulators for the efficacy of synaptic transmission. We analyzed mice overexpressing TrkC (TgNTRK3) for synaptic plasticity and the expression of glutamate receptor subunits. Animals were conditioned using a trace [conditioned stimulus (CS), tone; unconditioned stimulus (US), shock] paradigm. A single electrical pulse presented to the Schaffer collateral-commissural pathway during the CS-US interval evoked a monosynaptic field EPSP (fEPSP) at ipsilateral CA1 pyramidal cells. In wild types, fEPSP slopes increased across conditioning sessions and decreased during extinction, being linearly related to learning evolution. In contrast, fEPSPs in TgNTRK3 animals reached extremely high values, not accompanied with a proportionate increase in their learning curves. Long-term potentiation evoked in conscious TgNTRK3 was also significantly longer lasting than in wild-type mice. These functional alterations were accompanied by significant changes in NR1 and NR2B NMDA receptor subunits, with no modification of NR1(Ser 896) or NR1(Ser 897) phosphorylation. No changes of AMPA and kainate subunits were detected. Results indicate that the NT-3/TrkC cascade could regulate synaptic transmission and plasticity through modulation of glutamatergic transmission at the CA3-CA1 synapse.
Journal of Neuroscience 03/2007; 27(9):2253-60. · 7.11 Impact Factor
-
Mara Dierssen,
Mònica Gratacòs, Ignasi Sahún,
Miguel Martín,
Xavier Gallego,
Alejandro Amador-Arjona,
María Martínez de Lagrán,
Patricia Murtra,
Eulalia Martí,
Miguel A. Pujana,
Isidre Ferrer,
Esther Dalfó,
Carmen Martínez-Cué,
Jesús Flórez,
Jesús F. Torres-Peraza,
Jordi Alberch,
Rafael Maldonado,
Cristina Fillat,
Xavier Estivill
[show abstract]
[hide abstract]
ABSTRACT: Accumulating evidence has suggested that neurotrophins participate in the pathophysiology of mood disorders. We have developed transgenic mice overexpressing the full-length neurotrophin-3 receptor TrkC (TgNTRK3) in the central nervous system. TgNTRK3 mice show increased anxiety-like behavior and enhancement of panic reaction in the mouse defense test battery, along with an increase in the number and density of catecholaminergic (tyrosine hydroxylase positive) neurons in locus coeruleus and substantia nigra. Furthermore, treatment of TgNTRK3 mice with diazepam significantly attenuated the anxiety-like behaviors in the plus maze. These results provide evidence for the involvement of TrkC in the development of noradrenergic neurons in the central nervous system with consequences on anxiety-like behavior and panic reaction. Thus, changes in TrkC expression levels could contribute to the phenotypic expression of panic disorder through a trophic effect on noradrenergic neurons in the locus coeruleus. Our results demonstrate that the elevated NT3-TrkC tone via overexpression of TrkC in the brain may constitute a molecular mechanism for the expression of anxiety and anxiety.
Neurobiology of Disease 12/2006; 24(2):403-418. · 5.40 Impact Factor
