RESUMEN
Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Cav1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Cav1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Cav1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Cav1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.
Asunto(s)
Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/fisiología , Trastornos Mentales/genética , Adulto , Negro o Afroamericano , Animales , Trastorno Bipolar/genética , Canales de Calcio/genética , Trastorno Depresivo Mayor/genética , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Humanos , Masculino , Ratones/embriología , Ratones Transgénicos/genética , Neuronas/metabolismo , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genéticaRESUMEN
Anxiety disorders constitute a major disease and social burden worldwide; however, many questions concerning the underlying molecular mechanisms still remain open. Besides the involvement of the major excitatory (glutamate) and inhibitory (gamma aminobutyric acid (GABA)) neurotransmitter circuits in anxiety disorders, the stress system has been directly implicated in the pathophysiology of these complex mental illnesses. The glucocorticoid receptor (GR) is the major receptor for the stress hormone cortisol (corticosterone in rodents) and is widely expressed in excitatory and inhibitory neurons, as well as in glial cells. However, currently it is unknown which of these cell populations mediate GR actions that eventually regulate fear- and anxiety-related behaviors. In order to address this question, we generated mice lacking the receptor specifically in forebrain glutamatergic or GABAergic neurons by breeding GRflox/flox mice to Nex-Cre or Dlx5/6-Cre mice, respectively. GR deletion specifically in glutamatergic, but not in GABAergic, neurons induced hypothalamic-pituitary-adrenal axis hyperactivity and reduced fear- and anxiety-related behavior. This was paralleled by reduced GR-dependent electrophysiological responses in the basolateral amygdala (BLA). Importantly, viral-mediated GR deletion additionally showed that fear expression, but not anxiety, is regulated by GRs in glutamatergic neurons of the BLA. This suggests that pathological anxiety likely results from altered GR signaling in glutamatergic circuits of several forebrain regions, while modulation of fear-related behavior can largely be ascribed to GR signaling in glutamatergic neurons of the BLA. Collectively, our results reveal a major contribution of GRs in the brain's key excitatory, but not inhibitory, neurotransmitter system in the regulation of fear and anxiety behaviors, which is crucial to our understanding of the molecular mechanisms underlying anxiety disorders.
Asunto(s)
Trastornos de Ansiedad/fisiopatología , Receptores de Glucocorticoides/metabolismo , Receptores de Glutamato/metabolismo , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/fisiopatología , Complejo Nuclear Basolateral/metabolismo , Corticosterona/metabolismo , Fármacos actuantes sobre Aminoácidos Excitadores/metabolismo , Miedo/fisiología , GABAérgicos/metabolismo , Neuronas GABAérgicas/metabolismo , Ácido Glutámico/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Ratones , Ratones Noqueados , Neuronas/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Prosencéfalo/metabolismo , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Expression of the lacZ-sequence is a widely used reporter-tool to assess the transgenic and/or transfection efficacy of a target gene in mice. Once activated, lacZ is permanently expressed. However, protein accumulation is one of the hallmarks of neurodegenerative diseases. Furthermore, the protein product of the bacterial lacZ gene is ß-galactosidase, an analog to the mammalian senescence-associated ß-galactosidase, a molecular marker for aging. Therefore we studied the behavioral, structural and molecular consequences of lacZ expression in distinct neuronal sub-populations. lacZ expression in cortical glutamatergic neurons resulted in severe impairments in hippocampus-dependent memory accompanied by marked structural alterations throughout the CNS. In contrast, GFP expression or the expression of the ChR2/YFP fusion product in the same cell populations did not result in either cognitive or structural deficits. GABAergic lacZ expression caused significantly decreased hyper-arousal and mild cognitive deficits. Attenuated structural and behavioral consequences of lacZ expression could also be induced in adulthood, and lacZ transfection in neuronal cell cultures significantly decreased their viability. Our findings provide a strong caveat against the use of lacZ reporter mice for phenotyping studies and point to a particular sensitivity of the hippocampus formation to detrimental consequences of lacZ expression. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Hipocampo/metabolismo , Operón Lac , Memoria/fisiología , Neuronas/metabolismo , beta-Galactosidasa/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Supervivencia Celular/fisiología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Expresión Génica , Ácido Glutámico/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Integrasas/genética , Integrasas/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/patología , Proteínas Recombinantes de Fusión/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
A massive gelatinous ascites occurred in a 60-year-old patient, with no primary tumor found in the clinical work-up. The malignant cells were not found in the cytological examination of ascites. Explorative laparotomy revealed a gelatinous mass of 14 kg, a cystic tumor of the omentum and an identical cystic tumor of the spleen's lower pole. It was a well differentiated mucinous cystadenocarcinoma, most likely originating in the appendix. Most interesting is the involvement of the spleen with mucinous epithelial cysts, described as a rare finding associated with pseudomyxoma.