RESUMEN
Widespread release of norepinephrine (NE) throughout the forebrain fosters learning and memory via adrenergic receptor (AR) signaling, but the molecular mechanisms are largely unknown. The ß2 AR and its downstream effectors, the trimeric stimulatory Gs-protein, adenylyl cyclase (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca2+ channel (LTCC) CaV1.2. Phosphorylation of CaV1.2 by PKA on Ser1928 is required for the upregulation of Ca2+ influx on ß2 AR stimulation and long-term potentiation induced by prolonged theta-tetanus (PTT-LTP) but not LTP induced by two 1-s-long 100-Hz tetani. However, the function of Ser1928 phosphorylation in vivo is unknown. Here, we show that S1928A knock-in (KI) mice of both sexes, which lack PTT-LTP, express deficiencies during initial consolidation of spatial memory. Especially striking is the effect of this mutation on cognitive flexibility as tested by reversal learning. Mechanistically, long-term depression (LTD) has been implicated in reversal learning. It is abrogated in male and female S1928A knock-in mice and by ß2 AR antagonists and peptides that displace ß2 AR from CaV1.2. This work identifies CaV1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD.SIGNIFICANCE STATEMENT We show that phosphorylation of the Ca2+ channel CaV1.2 on Ser1928 is important for consolidation of spatial memory and especially its reversal, and long-term depression (LTD). Identification of Ser1928 as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory.
Asunto(s)
Plasticidad Neuronal , Memoria Espacial , Ratones , Masculino , Femenino , Animales , Plasticidad Neuronal/fisiología , Potenciación a Largo Plazo/fisiología , Transducción de Señal , Fosforilación , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Hipocampo/fisiologíaRESUMEN
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some carriers of the fragile X premutation (PM). In PM carriers, there is a moderate expansion of a CGG trinucleotide sequence (55-200 repeats) in the fragile X gene (FMR1) leading to increased FMR1 mRNA and small to moderate decreases in the fragile X mental retardation protein (FMRP) expression. The key symptoms of FXTAS include cerebellar gait ataxia, kinetic tremor, sensorimotor deficits, neuropsychiatric changes, and dementia. While the specific trigger(s) that causes PM carriers to progress to FXTAS pathogenesis remains elusive, the use of animal models has shed light on the underlying neurobiology of the altered pathways involved in disease development. In this review, we examine the current use of mouse models to study PM and FXTAS, focusing on recent advances in the field. Specifically, we will discuss the construct, face, and predictive validities of these PM mouse models, the insights into the underlying disease mechanisms, and potential treatments.
Asunto(s)
Ataxia/fisiopatología , Modelos Animales de Enfermedad , Síndrome del Cromosoma X Frágil/fisiopatología , Actividad Motora/fisiología , Temblor/fisiopatología , Animales , Ataxia/tratamiento farmacológico , Ataxia/genética , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/genética , Humanos , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Temblor/tratamiento farmacológico , Temblor/genéticaRESUMEN
14-3-3 is a family of regulatory proteins highly expressed in the brain. Previous invertebrate studies have demonstrated the importance of 14-3-3 in the regulation of synaptic functions and learning and memory. However, the in vivo role of 14-3-3 in these processes has not been determined using mammalian animal models. Here, we report the behavioral and electrophysiological characterization of a new animal model of 14-3-3 proteins. These transgenic mice, considered to be a 14-3-3 functional knock-out, express a known 14-3-3 inhibitor in various brain regions of different founder lines. We identify a founder-specific impairment in hippocampal-dependent learning and memory tasks, as well as a correlated suppression in long-term synaptic plasticity of the hippocampal synapses. Moreover, hippocampal synaptic NMDA receptor levels are selectively reduced in the transgenic founder line that exhibits both behavioral and synaptic plasticity deficits. Collectively, our findings provide evidence that 14-3-3 is a positive regulator of associative learning and memory at both the behavioral and cellular level.
Asunto(s)
Proteínas 14-3-3/fisiología , Aprendizaje por Asociación/fisiología , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Memoria/fisiología , Proteínas 14-3-3/deficiencia , Animales , Reacción de Prevención/fisiología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Condicionamiento Psicológico/fisiología , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/genética , Miedo/fisiología , Hipocampo/metabolismo , Técnicas In Vitro , Potenciación a Largo Plazo/genética , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Técnicas de Placa-ClampRESUMEN
The aggresome is a key cytoplasmic organelle for sequestration and clearance of toxic protein aggregates. Although loading misfolded proteins cargos to dynein motors has been recognized as an important step in the aggresome formation process, the molecular machinery that mediates the association of cargos with the dynein motor is poorly understood. Here, we report a new aggresome-targeting pathway that involves isoforms of 14-3-3, a family of conserved regulatory proteins. 14-3-3 interacts with both the dynein-intermediate chain (DIC) and an Hsp70 co-chaperone Bcl-2-associated athanogene 3 (BAG3), thereby recruiting chaperone-associated protein cargos to dynein motors for their transport to aggresomes. This molecular cascade entails functional dimerization of 14-3-3, which we show to be crucial for the formation of aggresomes in both yeast and mammalian cells. These results suggest that 14-3-3 functions as a molecular adaptor to promote aggresomal targeting of misfolded protein aggregates and may link such complexes to inclusion bodies observed in various neurodegenerative diseases.
Asunto(s)
Proteínas 14-3-3/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas 14-3-3/genética , Dineínas , Chaperonas Moleculares/genética , Pliegue de Proteína , Proteínas/metabolismo , TransfecciónRESUMEN
OBJECTIVE: To describe in this review how research using mouse models developed to study the Fragile X premutation (PM) and Fragile X-associated tremor/ataxia syndrome (FXTAS) have contributed to understanding these disorders. PM carriers bear an expanded CGG trinucleotide repeat on the Fragile X Mental Retardation 1 (FMR1) gene, and are at risk for developing the late onset neurodegenerative disorder FXTAS. CONCLUSIONS: Much has been learned about these genetic disorders from the development and study of mouse models. This includes new insights into the early cellular and molecular events that occur in PM carriers and in FXTAS, the presence of multiorgan pathology beyond the CNS, immunological dysregulation, unexpected synthesis of a potentially toxic peptide in FXTAS (i.e., FMRpolyG), and evidence that the disease process may be halted or reversed by appropriate molecular therapies given early in the course of disease.
Asunto(s)
Ataxia/genética , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Mutación/genética , Temblor/genética , Animales , Ataxia/patología , Síndrome del Cromosoma X Frágil/patología , Humanos , Masculino , Ratones , Pruebas Neuropsicológicas , Temblor/patología , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
BACKGROUND: The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia. METHODS: We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. RESULTS: We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3-3 FKO mice display other behavioral deficits that correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. In particular, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics secondary to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin. CONCLUSIONS: Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.
Asunto(s)
Proteínas 14-3-3/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Transmisión Sináptica , Proteínas 14-3-3/antagonistas & inhibidores , Proteínas 14-3-3/genética , Animales , Antipsicóticos/administración & dosificación , Conducta Animal/efectos de los fármacos , Cateninas/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Clozapina/administración & dosificación , Cofilina 1/metabolismo , Dendritas/metabolismo , Dendritas/patología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Haloperidol/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Inhibición Prepulso/efectos de los fármacos , Proteínas/genética , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/genética , Catenina deltaRESUMEN
14-3-3 proteins were originally discovered as a family of proteins that are highly expressed in the brain. Through interactions with a multitude of binding partners, 14-3-3 proteins impact many aspects of brain function including neural signaling, neuronal development and neuroprotection. Although much remains to be learned and understood, 14-3-3 proteins have been implicated in a variety of neurological disorders based on evidence from both clinical and laboratory studies. Here we will review previous and more recent research that has helped us understand the roles of 14-3-3 proteins in both neurodegenerative and neuropsychiatric diseases.